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The Hyperglycemia: Intensive Insulin Infusion in Infarction (HI-5) study: a randomized controlled trial of insulin infusion therapy for myocardial infarction.

OBJECTIVE: There is conflicting evidence regarding the benefit of intravenous insulin therapy on mortality following acute myocardial infarction (AMI). The goal of the current study was to determine whether improved glycemic control, achieved through an insulin/dextrose infusion with a variable rate of insulin, reduces mortality among hyperglycemic patients with AMI. RESEARCH DESIGN AND METHODS: Subjects suffering AMI with either known diabetes or without diabetes but blood glucose level (BGL) > or =7.8 mmol/l were randomized to receive insulin/dextrose infusion therapy for at least 24 h to maintain a BGL <10 mmol/l or conventional therapy. RESULTS: A total of 240 subjects were recruited. Insulin/dextrose infusion did not reduce mortality at the inpatient stage (4.8 vs. conventional 3.5%, P = 0.75), 3 months (7.1 vs 4.4%, P = 0.42), or 6 months (7.9 vs. 6.1%, P = 0.62). There was, however, a lower incidence of cardiac failure (12.7 vs. 22.8%, P = 0.04) and reinfarction within 3 months (2.4 vs. 6.1%, P = 0.05). When analyzed by mean BGL achieved during the first 24 h, mortality was lower among subjects with a mean BGL < or =8 mmol/l, compared with subjects with a mean BGL >8 mmol/l (2 vs. 11% at 6 months, P = 0.02). CONCLUSIONS: We did not find a reduction in mortality among patients who received insulin/dextrose infusion therapy. However, it remains possible that tight glycemic control with insulin therapy following AMI improves outcomes.

Blood Glucose↗

[Characteristics, management and prognosis of acute myocardial infarction in Israel in the 1990s. Israeli Survey Group on Acute Myocardial Infarction].

From 1990 to 1996 we conducted consecutive 2-month surveys in all CCUs (n = 26) in Israel. The aim was to compare the characteristics, management, and prognosis of patients with acute myocardial infarction (AMI) between the 4 surveys. Patient characteristics were similar in all surveys. About 75% of patients were males and had a first MI. Mechanical and arrhythmic complications decreased slightly between 1990 and 1996. In contrast, frequency of treatment with thrombolysis, aspirin, beta-blockers and ACE-I, as well as coronary interventional procedures, increased tremendously. In parallel, 30-day and 1-year mortality decreased significantly, from 16.5% and 22.5%, respectively, to 9.0% and 13.9%. After multiple adjustment for factors associated with mortality, the 30-day relative risk of death for patients hospitalized in 1992, 1994 and 1996 was 0.79 (95% CI 0.59-1.08), 0.75 (95% CI 0.56-1.01) and 0.54 (95% CI 0.39-9.74), respectively, as compared with 1990. Although there is no direct proof that changes in management of AMI are related to the reduction in mortality seen during the course of the surveys, the association seems likely.

Female↗

[Medico-social aspects of the post-infarct state. Clinical, functional, psychological and return-to-work studies of 100 patients with myocardial infarct treated in the coronary unit].

To determine whether intensive care unit are able to improve long term as well as immediate prognosis of acute myocardial infarction, one hundred patients, aged 40 to 60 years, six months to three years after discharge have been studied. All patients were examined with ergometric test, psychological assessment and medico-social survey. Comparison was made with patients treated in general medical wards. Correlations between clinical picture, psychological pattern, functional capacity and return to work prove that treatment in a coronary care unit positively affects the future of these patients. The importance of a rehabilitation program and its principles are also discussed.

Adult↗

[Changes in the specific activity and content of free nucleotides and polyamines of the infarct and pre-infarct area of the revascularized dog heart].

Changes on specific radioactivity and levels of free nucleotides and polyamines in infarcted and borderline tissue of reperfused dog heart. The changes on specific radioactivity and levels of free nucleotides and polyamines, spermine and spermidine, of reperfused heart show a different behaviour of the anoxic myocardium. An increase of both specific activity and levels of free nucleotides and polyamines after 30 minutes of ischemia is observed. A longer period of anoxia (6 hours) causes a decreased synthesis and concentration of free nucleotides and polyamines. A remarkable recovery of specific activity of these compounds after reperfusion is noted. The borderline tissue shows a similar behaviour but with smaller changes. Therefore, in our experimental conditions, ischemia does not cause an irreversible alteration in protein synthesis mechanism of myocardial cells. In addition, the reperfusion may cause a recovery of biochemical mechanisms that control the functional capacity of the cell. The polyamine changes may postulate a central role of these amines in both anoxic and reperfused heart.

Animals↗

[Dyslipidemia-related risk factors for myocardial infarction and polymorphism of ApoE gene among myocardial infarction patients and their siblings].

OBJECTIVE: To assess the risk factors of myocardial infarction (MI) and the polymorphism of the gene Apoliprotein (ApoE) genotype among MI patients and their siblings. METHODS: Questionnaire survey and clinical examination were conducted to 65 male MI patients, 141 "healthy" male siblings of the MI patients, and 47 healthy persons matched in age and sex. RESULTS: (1) The medians of TC, TG, LDL-C, TC/HDL-C in MI group and sibling group were higher than those in the control group with statistical significance. (2) BMI > 25 kg/m(2), cigarette > 10/d, TC > 5.2 mmol/L, TG > 2.26 mmol/L, LDL-C > 3.4 mmol/L, TC/HDL-C > 5.0, and FBG > 5.6 mmol/L were risk factors for MI; and HDL-C > 0.9 mmol/L was a protective factor for MI. (3) Among the three genotypes of ApoE, E3/3 was the commonest one. However, no significant difference was found in the distribution frequencies of these 3 genotypes, levels of serum lipid and lipoprotein, and TC/HDL-C. (4) Among the MI patients the number of allele E4 carrier was nearly twice the number of the non-allele E4 carrier. CONCLUSION: Dyslipidemia is an important risk factor for MI, and polymorphism of ApoE may be an indirect risk factor of coronary heart disease genetically.

Adult↗

ISIS-3: a randomised comparison of streptokinase vs tissue plasminogen activator vs anistreplase and of aspirin plus heparin vs aspirin alone among 41,299 cases of suspected acute myocardial infarction. ISIS-3 (Third International Study of Infarct Survival) Collaborative Group.

41,299 patients entering 914 hospitals up to 24 h (median 4 h) after the onset of suspected acute myocardial infarction were randomised between streptokinase (SK: 1.5 MU infused over about 1 h), tissue plasminogen activator (tPA, duteplase: 0.60 MU/kg infused over about 4 h), or anisoylated plasminogen-streptokinase activator complex (APSAC), anistreplase: 30 U over about 3 min). All patients were to receive aspirin (162 mg/day enteric-coated), with the first tablet chewed for rapid and full antiplatelet effect. Half of all patients were randomly allocated subcutaneous calcium heparin (12,500 IU starting at 4 h and given twice daily for 7 days or until prior discharge) in addition to aspirin, and the other half were to receive aspirin alone. ASPIRIN PLUS HEPARIN VERSUS ASPIRIN ALONE--The addition of heparin to aspirin was associated with an excess of transfused or other major non-cerebral bleeds (1.0% aspirin plus heparin vs 0.8% aspirin alone; 2p < 0.01) and of definite or probable cerebral haemorrhage (0.56% vs 0.40%; 2p < 0.05), but with no significnat differences in total stroke (1.28% vs 1.18%). Reinfarctions were slightly less common among those allocated aspirin plus heparin (3.16% vs 3.47%; 2p = 0.09). There was no signficant difference in the pre-specified endpoint of 35-day mortality (2132 [10.3%] aspirin plus heparin vs 2189 [10.6%] aspirin alone). During the scheduled heparin treatment period there were slightly fewer deaths in the aspirin plus heparin group (days 0-7 in hospital: 1534 [7.4%] vs 1633 [7.9%]; 2 p = 0.06), with a slight convergence by day 35 (598 further deaths [3.1% of survivors] vs 556 [2.9%]). The pattern was similar to that observed in the GISSI-2 trial, so that in both trials combined there was a significant reduction in mortality during the scheduled treatment period (2071 [6.8%] vs 2239 [7.3%]; 2p < 0.01). This indicates avoidance of 5 deaths (SD 2) per 1000 patients allocated this high-dose subcutaneous heparin regimen in addition to aspirin, but some of any early benefit may be lost after heparin ceases, with no significant mortality advantage in days 0-35 (both trials: 3100 [10.0%] vs 3172 [10.2%]) or during follow-up to 6 months. SK VERSUS APSAC--APSAC was associated with significantly more reports of allergy causing persistent symptoms and of non-cerebral bleeds, but not of transfused bleeds or of reinfarctions. There was a slight excess of strokes with APSAC (1.04% SK vs 1.26% APSAC; 2p = 0.08), much of it appearing soon after treatment started (strokes during days 0-1: 0.50% SK vs 0.73% APSAC; 2p < 0.02) and being attributed to cerebral haemorrhage (0.24% SK vs 0.55% APSAC; 2p < 0.0001). No significant difference was observed in reinfarction (3.47% SK vs 3.55% APSAC). There was no significant mortality difference during days 0-35, either among all randomised patients (1455 [10.6%] SK vs 1448 [10.5%] APSAC) or among the pre-specified subset presenting within 0-6 h of pain onset and with ST elevation on the electrocardiogram in whom fibrinolytic treatment may have most to offer (861 [10.0%] SK vs 855 [9.9%] APSAC). No significant difference in 6-month survival was apparent overall or in the subset.(ABSTRACT TRUNCATED AT 400 WORDS)

Aged↗

Long-term adaptation of 24-h heart rate variability after myocardial infarction. The EAMI Study Group. Exercise Training in Anterior Myocardial Infarction.

To investigate the effects of physical training on neurovegetative profile of patients with previous anterior myocardial infarction (MI), we studied 38 patients out of the EAMI study at 4 to 6 weeks after anterior MI (test 1), who were then assigned randomly to a training group (n = 22) or to a control group (n = 16) and studied again 6 months later (test 2). Neurovegetative function was assessed by analyzing the heart rate variability (HRV) of 24 h, from ambulatory ECG recording, both in time domain, as standard deviation of sinus rhythm RR intervals (sdRR) and percentage of differences greater than 50 ms for successive sinus rhythm R-R intervals (pNN50), and in frequency domain, as low frequency (LF) and high frequency (HF) components of RR variability power spectrum. At test 1, HRV was almost in normal range or slightly decreased in few subjects. HRV increased on average at test 2: sdRR augmented significantly (p less than 0.05) without significant differences between training group and control group; mean LF/HF ratio increased slightly (p less than 0.05) at test 2. This might suggest a shift of neurovegetative balance toward a sympathetic rule, but the difference is too small and the patient population limited to reach firm conclusions. Analysis of 24-h dynamics of HRV in single patients showed different patterns and different adaptations during the time course of 6 months after anterior MI.

Adaptation, Physiological↗

Antioxidant effects of combined vitamins C and E in acute myocardial infarction. The randomized, double-blind, placebo controlled, multicenter pilot Myocardial Infarction and VITamins (MIVIT) trial.

AIMS: There is a large body of evidence that reactive oxygen species (ROS) produced during myocardial ischemia and reperfusion play a crucial role in myocardial damage and endothelial dysfunction. The MIVIT pilot trial was designed to test the effects of antioxidant vitamins C and E on the clinical outcome of patients with AMI. METHODS AND RESULTS: In this randomized, double-blind, multicenter trial, 800 patients (mean age 62) with AMI were randomly allocated to receive, on top of routine medication, one of two treatments: vitamin C (1000 mg/12 h infusion) followed by 1200 mg/24 h orally and vitamin E (600 mg/24 h) or matching placebo for 30 days. Primary end point (composite of in-hospital cardiac mortality, non-fatal new myocardial infarction, VT/VF/asystole, shock/pulmonary edema) occurred less frequently in patients treated with antioxidants (55 [14%] vs 75 [19%], OR 0.82 [95% CI, 0.68-1.00], p=0.048). CONCLUSIONS: This randomized pilot trial shows that supplementation with antioxidant vitamins is safe and seems to positively influence the clinical outcome of patients with AMI. A larger study is warranted to provide further evidence of this promising and inexpensive regimen.

Adult↗

Streptokinase-induced hypotension has no detrimental effect on patients with thrombolytic treatment for acute myocardial infarction. A substudy of the Romanian Study for Accelerated Streptokinase in Acute Myocardial Infarction (ASK-ROMANIA).

UNLABELLED: The Streptokinase (SK) regimen (1.5 MU/60 minutes) has remained unchanged for the past 20 years in patients with ST-segment elevation acute myocardial infarction (STEMI) due to fear of hypotension (a specific effect of this thrombolytic agent) and of hemorrhagic complications. OBJECTIVE: To evaluate the influence of the Streptokinase-induced hypotension (SK-hTA) on the rate of coronary reperfusion (CR), incidence of cardiogenic shock (CS), 30-day mortality and incidence of stroke in patients (pts.) with STEMI. The SK-hTA was defined as decrease of the systolic blood pressure with at least 20% within the first 20 min. after the start of the SK infusion. METHODS: A group of 837 pts. (age 20-90) with thrombolytic treatment, with three "accelerated" SK regimens within the first 6 hours after the onset of STEMI and enrolled in the Romanian open, prospective, non-randomised study for accelerated SK in STEMI (ASK-ROMANIA) have been included. The SK regimens consisted in infusing of the standard dose of 1.5 M.U. either in 30 min. (regimen SK1.5/30, 173 pts).) or in 20 min. (regimen SK1.5/20, 377 pts.) or of the half dose (0.75 M.U.) in 10 min. followed by a new infusion of 0.75 M.U. after 50 min. only if no bed-side signs of CR have been recorded (regimen SK 0.75/10, 287 pts.). The speed of the SK infusion was maintained in all pts. experiencing SK-hTA. All pts. received aspirin and heparin or enoxaparin if not contraindicated. Three noninvasive CR criteria have been used: 1. Rapid cessation of the chest pain. 2. Rapid decrease of the ST segment elevation by more than 50% of the initial value. 3. Rapid increase of the CK and CK-MB with a peak within the first 12 hrs. RESULTS: SK-hTA appeared in 372 pts. (44.55%) at 9+/-5 min after the start of the SK infusion. In this subgroup the rate of CR was 74.46%, non-significantly higher than the one of 68.81% registered in pts. without SK-hTA (p=0.071). SK-hTA disappeared in all patients after 16+/-6 minutes without a specific therapy. Fourteen pts. with SK-hTA (3.76%) and 16 pts. without SK-hTA (3.44%) developed CS after thrombolysis ( non-significant difference). The global in-hospital mortality was 10.21% in pts. with SK-hTA and 9.89% in pts. without this side effect (non-significant difference). The incidences of hemorrhagic and ischemic strokes were 0.26% (1 patient) respectively 0.52% (2 pts.) in the SK-hTA subgroup and 0.43% (2 pts.) respectively 0.64% (3 pts.) in the subgroup without SK-hTA. CONCLUSIONS: 1. Despite a very high incidence (44.55%) the SK-hTA has not a detrimental effect in pts. treated with accelerated SK regimens for STEMI. 2. Streptokinase can be rapidly administered without an increased risk.

Adult↗

[Impact of reperfusion strategies on in-hospital outcome in ST-elevation myocardial infarction in a context of interhospital network: data from the prospective VENERE registry (VENEto acute myocardial infarction REgistry].

BACKGROUND: Primary angioplasty (pPCI) is the most effective reperfusion treatment of acute ST-elevation myocardial infarction (STEMI), but logistic- and organization-related problems could affect the outcome. The aim of this study was to investigate the in-hospital outcome according to reperfusion strategy in the Veneto Region cardiology network. METHODS: A treatment protocol, aimed to treat patients with high-risk STEMI by pPCI on-site or after transport, was developed and shared by the majority of cardiology departments in the Veneto Region. Data of all consecutive patients with STEMI were prospectively recorded during a 6-month period. RESULTS: 999 patients with symptom onset < 12 hours were admitted to the 28 participating hospitals: 860 were treated on-site and 139 were transferred from the admitting hospital to an interventional center for PCI. Overall, 82% of patients were treated with reperfusion therapy. Ten patients died immediately before any treatment could be initiated. In 170 patients who did not receive any reperfusion treatment, in 302 patients who received fibrinolysis (and eventually rescue PCI) and in 517 patients sent to pPCI, the following in-hospital outcome was observed respectively: mortality rate 10, 6.95 and 6.57%; reinfarction rate 0.6, 1 and 0.4%; incidence of stroke 1.7, 1.4 and 0.9%; the need for urgent revascularization procedure 6.5, 10 and 2.3%. After adjustment for confounding variables, the in-hospital occurrence of the combined events was significantly lower in patients treated with pP-CI (odds ratio 0.33, confidence interval 0.20-0.53, p < 0.01) as well as a trend for a reduced in-hospital mortality was observed (odds ratio 0.51, confidence interval 0.26-1.03, p = 0.06). CONCLUSIONS: In the VENERE registry, patients treated with pPCI had a better in-hospital outcome as compared to those treated with fibrinolytic strategy.

Aged↗

[Hospital epidemiology of ST-segment elevation myocardial infarction and feasibility of primary percutaneous coronary intervention in an interhospital network: data from a multicenter, prospective and observational study VENERE (VENEto acute myocardial infarction REgistry].

BACKGROUND: Primary percutaneous coronary intervention (pPCI) is the most effective reperfusion treatment of acute ST-segment elevation myocardial infarction (STEMI), but logistic- and organization-related problems affect its feasibility. The aim of this study was to investigate a) the requirements of reperfusion therapies, and b) the feasibility of pPCI as suggested by the current guidelines, in the Veneto Region. METHODS: With the aim to treat with pPCI most of the patients with high-risk STEMI regardless of the type of admitting hospital, a single treatment protocol was developed and shared by the majority of Cardiology Departments in the Veneto Region. Data of all consecutive patients with STEMI were prospectively recorded and subsequently and independently compared with administrative data. RESULTS: In 28 participating hospitals, 1160 consecutive patients with STEMI were enrolled during a 6-month period: in 999 symptom onset was < 12 hours. Based on the registry data, it is possible to estimate that 697 patients/million of inhabitants/year are admitted in Cardiology Departments with the initial diagnosis of STEMI: 86% are admitted < 12 hours from symptom onset and 58% of them have at least one characteristic of high risk. The strategy of immediate coronary angiography and possible PCI was carried out in 52.3% of eligible patients: in 55.8 and 47.5% of high- and low-risk STEMI and from 17.1 to 75.1% based on the type of admitting hospital. Recanalization with pPCI was obtained < 90 min from the diagnosis in 70 and 32% of patients treated on site and transferred, respectively. CONCLUSIONS: The absolute number of patients with STEMI eligible for reperfusion therapies is lower than previously reported. The reperfusion strategy based on pPCI was much more related to the type of admitting hospital than to the clinical characteristics of the patients. pPCI performed as suggested by the current guidelines is feasible in patients admitted in hospitals with interventional facilities available 24 hours/day, but in those who need to be transferred it is necessary to modify the existing pathways and/or treatment protocols.

Angioplasty, Balloon, Coronary↗

[Prevalence of late potentials in acute myocardial infarction and its relation to ventricular arrhythmias in early period of acute myocardial infarction (AMI)].

The prevalence of ventricular late potentials (LP) in acute myocardial infarction (AMI) and the relationship between the presence of LP and the occurrence of spontaneous sustained ventricular tachycardia (VT) or fibrillation (VE) in the early phase (within 10 days) of AMI were studied. A total of 251 consecutive patients who had an uninterrupted natural history before special treatment formed this study. Sustained VT or VF occurred in 20 patients (8%). LP were recorded in 67 patients (27%). The incidence of LP was significantly higher among patients with VT/VF than among those without VT/VF (12 of 20, or 60%, vs 55 of 231, or 24%, P less than 0.01). The subgroup of patients whose VT/VF occurred within 1 hour of onset of AMI also showed a higher incidence of LP (5 of 9, or 56%, vs 55 of 231, or 24%, P less than 0.05). The results showed that the mechanism of VT/VF in early period including those happened within 1 hour of onset of AMI in man is due to reentry, and that LP can help to identify those high risk patients with a propensity to develop VT/VF in early period of AMI.

Electrocardiography↗

[Comparison of the course of myocardial infarction and post-infarction morbidity among urban and rural populations in the Kielce region].

An analysis is made of the course of myocardial infarct and the post-hospital period of the illness in 997 patients from the Kielce Region who were hospitalized in the Clinical Department of Cardiology in the years 1977-1985. The patients were classified into three groups: I--a group of 226 patients who have resided in town since birth, II--a group of 507 patients who resided in the rural areas till the age 14-18 years and who later moved to towns, and III--a group of 264 patients who have lived in rural areas since birth. All the three groups were comparable with one another with respect to the proportion of hospitalized men and women, the average age of hospitalized men and women, frequency of occurrence of supraventricular and ventricular arrhythmias in the course of the hospital phase of illness, hospital death rate up to the age of 70 years, an increased proportion of hospital death rate of women in relation to that of men and the structures of causes of death during the hospital period of illness. The main differences concerned: a markedly lower hospital death rate in the group of rural population over the age of 70 (p less than 0.001), a markedly more frequent occurrence of the risk factors of ischaemic heart disease in the group of urban population, and a markedly more frequent occurrence of block A-V IIIo and the arrhythmia disturbances of intraventricular conduction in the group of rural population. Hospital death rate in the analyzed period was 19.2%.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

Increases in alpha-but not beta-adrenoceptors in hypertrophied non-infarcted cardiac muscles from rats with chronic myocardial infarction.

The alteration in adrenoceptors in the hypertrophied right ventricle of the rats with myocardial infarction (Ml) was examined. The density of alpha-1-adrenoceptors increased in four and twelve week old Ml rats but not in one week old Ml rats. The beta-adrenoceptors did not significantly change. It is probable that the increased density of alpha-adrenoceptors may be one of the causes for the increased responsiveness to the alpha-adrenergic agonist in the hypertrophied cardiac muscles of Ml rats.

Animals↗

[Thrombolysis therapy and coronary angiography in acute myocardial infarct in the Augsburg region: results of the Augsburger Heart infarct register 1985-1987].

In the years 1985-87, the Augsburg Coronary Event Register registered 1333 hospitalized patients who had survived an acute myocardial infarction (AMI) for at least 24 h. In 953 patients, data on time intervals in the prehospital phase were documented in addition to the medical records data in a standardized nurse interview. The time from onset of AMI until the patient called for medical attention constituted most of the prehospital time delay. Of the interviewed male and female patients, 67% were hospitalized within 6 h (= time limit). The differences, both in the number of thrombolyses and the number of coronary angiographies performed in men and in women are statistically significant. Thrombolysis was performed in 27% of the male and 12% of the female AMI patients who were admitted to hospital within the time limit. The rate of thrombolytic therapy decreased with increasing age and was less in patients with recurrent AMI (men: 20%, women: 0%) than in patients with first AMI (men: 29%, women: 15%). There was some time-of-day variation in the percentage of thrombolytic therapy which may be attributable to hospital organization. From 1985 to 1987, the coronary angiography rates performed in the medical center doubled, independent of the thrombolytic therapy rates. In this time, angiography rates in thrombolyzed patients increased from 49% to 75%, and from 14% to 31% in patients without thrombolysis. The 28-day case fatality was 4.8% in patients with thrombolysis and 13% in patients without thrombolytic therapy. Controlling for age, sex, and recurrent AMI, this difference is not statistically significant.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

Randomised trial of intravenous atenolol among 16 027 cases of suspected acute myocardial infarction: ISIS-1. First International Study of Infarct Survival Collaborative Group.

Between mid-1981 and Jan 1, 1985, 16 027 patients entering 245 coronary care units at a mean of 5.0 h after the onset of suspected acute myocardial infarction were randomised either to a control group or to a group receiving atenolol (5-10 mg iv immediately, followed by 100 mg/day orally for 7 days). Vascular mortality during the treatment period (days 0-7) was significantly lower (2p less than 0.4) in the treated group, 313/8037 (3.89%) versus 365/7990 (4.57%), but this 15% difference has wide 95% confidence limits (from about zero to about a quarter). No subgroups were identified in which the proportional difference in days 0-7 was clearly better, or clearly worse, than 15%. After the treatment period, there was only a slight further divergence (691 vs 703 additional vascular deaths by Jan 1, 1985). Thus, overall vascular mortality was significantly lower in the atenolol group at one year (life-table estimates: 10.7% atenolol vs 12.0% control; 2p less than 0.01) but not at Jan 1, 1985 (crude percentages: 12.5% vs 13.4%; 2p less than 0.07). However, atenolol patients were more likely than controls to be discharged on beta-blockers, which can account for much of the additional difference in vascular mortality after day 7. Immediate beta-blockade increased the extent of inotropic drug use (5.0% vs 3.4%, 2p less than 0.0001), chiefly on days 0-1, but despite this most of the improvement in vascular mortality was seen during days 0-1 (121 vs 171 deaths). Treatment did not appear to decrease the number in whom cardiac enzymes rose to above twice the local upper limit of normal. Slightly fewer non-fatal cardiac arrests (189 vs 198) and reinfarctions (148 vs 161) were recorded in the atenolol group, neither difference being significant. Systematic review of fatal and of non-fatal events in ISIS-1 and in all other randomised trials of iv beta-blockade reinforces the suggestion that treatment reduces mortality in the first week by about 15%, but with a rather less extreme effect in days 0-1 than was observed in ISIS-1 alone. It also provides highly significant (2p less than 0.0002) evidence of an effect on the combined end-point of death, arrest, or reinfarction, suggesting that treatment of about 200 patients would lead to the avoidance of 1 reinfarction, 1 arrest, and 1 death during days 0-7. ISIS-1 suggests these early gains will persist.

Administration, Oral↗

Randomized factorial trial of high-dose intravenous streptokinase, of oral aspirin and of intravenous heparin in acute myocardial infarction. ISIS (International Studies of Infarct Survival) pilot study.

619 patients with suspected acute myocardial infarction (MI) were randomized to receive either a high-dose short-term intravenous infusion of streptokinase (1.5 MU over one hour) or placebo. Using a '2 X 2 X 2 factorial' design, patients were also randomized to receive either oral aspirin (325 mg on alternate days for 28 days) or placebo, and separately randomized to receive either intravenous heparin (1000 IU h-1 for 48 hours) or no heparin. Streptokinase (SK) was associated with a nonsignificant (NS) increase in non-fatal reinfarction (3.9% SK vs 2.9% placebo) and decrease in mortality (7.5% vs 9.7% in hospital plus 6.1% vs 8.7% after discharge). After SK, there were significantly fewer strokes (0.5% vs 2.4%; 2P less than 0.05), but significantly more minor adverse events (e.g. hypotension and bradycardia, allergies, bruises or minor bleeds, nausea). Aspirin was associated with fewer non-fatal reinfarctions (3.2% aspirin vs 3.9% placebo; NS), deaths (in hospital: 6.1% vs 10.5%; 2P less than 0.05, and after discharge: 7.0% vs 6.9%; NS), and strokes (0.3% vs 2.0%; NS). Heparin was associated with a decrease in reinfarction (2.2% heparin vs 4.9% no heparin; NS), though not in mortality (in hospital: 8.0% vs 8.5%; NS, and after discharge: 7.0% vs 6.9%; NS), and with a trend towards more strokes (1.6% vs 0.7%; NS) and more bruising and bleeding (14% vs 12%; NS). To assess more reliably the effects of aspirin and of this SK regimen on mortality, about 400 hospitals worldwide are now collaborating in a large (about 20,000 patients planned) randomized trial (ISIS-2), for which the present study was a pilot.

Administration, Oral↗

Randomised trial of intravenous streptokinase, oral aspirin, both, or neither among 17,187 cases of suspected acute myocardial infarction: ISIS-2. ISIS-2 (Second International Study of Infarct Survival) Collaborative Group.

17,187 patients entering 417 hospitals up to 24 hours (median 5 hours) after the onset of suspected acute myocardial infarction were randomised, with placebo control, between: (i) a 1-hour intravenous infusion of 1.5 MU of streptokinase; (ii) one month of 160 mg/day enteric-coated aspirin; (iii) both active treatments; or (iv) neither. Streptokinase alone and aspirin alone each produced a highly significant reduction in 5-week vascular mortality: 791/8592 (9.2%) among patients allocated streptokinase infusion vs 1029/8595 (12.0%) among those allocated placebo infusion (odds reduction: 25% SD 4; 2p less than 0.00001); 804/8587 (9.4%) vascular deaths among patients allocated aspirin tablets vs 1016/8600 (11.8%) among those allocated placebo tablets (odds reduction: 23% SD 4; 2p less than 0.00001). The combination of streptokinase and aspirin was significantly (2p less than 0.0001) better than either agent alone. Their separate effects on vascular deaths appeared to be additive: 343/4292 (8.0%) among patients allocated both active agents vs 568/4300 (13.2%) among those allocated neither (odds reduction: 42% SD 5; 95% confidence limits 34-50%). There was evidence of benefit from each agent even for patients treated late after pain onset (odds reductions at 0-4, 5-12, and 13-24 hours: 35% SD 6, 16% SD 7, and 21% SD 12 for streptokinase alone; 25% SD 7, 21% SD 7, and 21% SD 12 for aspirin alone; and 53% SD 8, 32% SD 9, and 38% SD 15 for the combination of streptokinase and aspirin). Streptokinase was associated with an excess of bleeds requiring transfusion (0.5% vs 0.2%) and of confirmed cerebral haemorrhage (0.1% vs 0.0%), but with fewer other strokes (0.6% vs 0.8%). These "other" strokes may have included a few undiagnosed cerebral haemorrhages, but still there was no increase in total strokes (0.7% streptokinase vs 0.8% placebo infusion). Aspirin significantly reduced non-fatal reinfarction (1.0% vs 2.0%) and non-fatal stroke (0.3% vs 0.6%), and was not associated with any significant increase in cerebral haemorrhage or in bleeds requiring transfusion. An excess of non-fatal reinfarction was reported when streptokinase was used alone, but this appeared to be entirely avoided by the addition of aspirin. Those allocated the combination of streptokinase and aspirin had significantly fewer reinfarctions (1.8% vs 2.9%), strokes (0.6% vs 1.1%), and deaths (8.0% vs 13.2%) than those allocated neither. The differences in vascular and in all-cause mortality produced by streptokinase and by aspirin remain highly significant (2p less than 0.001 for each) after the median of 15 months of follow-up thus far available.

Administration, Oral↗