Thrombolytic treatment in acute myocardial infarction. Choice of preparations in Norwegian hospitals

In 1994 Statens legemiddelkontroll recommended Norwegian hospitals to increase the use of recombinant tissue plasminogen activator (r-tPA) in thrombolytic treatment of acute myocardial infarction. Using a questionnaire, which was distributed to all medical departments in Norwegian hospitals, we examined and assessed the preference of thrombolytic agents. None of the coronary care units administered r-tPA routinely as their first choice. Of 59 hospitals involved, 35 (59%) considered r-tPA on a wider indication (i.e. young age, short history of symptoms, and anterior wall infarction) than the 24 (41%) that only used r-tPA when streptokinase had recently been given. Of a total of 11,191 cases of myocardial infarction in 1996, 628 (6%) were treated with r-tPA. Closer examination of 2,818 cases of myocardial infarction in 13 hospitals revealed that thrombolytic treatment was given in 1,016 (36%) instances. In 206 cases (20%), the chosen agent was r-tPA, whereas 810 (80%) were given streptokinase. The reasons for the preference of streptokinase to r-tPA are discussed.     

Metabolic modulation of acute myocardial infarction. The ECLA (Estudios Cardiológicos Latinoamérica) Collaborative Group

BACKGROUND: Several trials have been performed in the past using glucose, insulin, and potassium infusion (GIK) for the treatment of acute myocardial infarction (AMI). Because of continuing uncertainty about the potential role of this therapeutic intervention, we conducted a randomized trial to evaluate the impact of a GIK solution during the first hours of AMI. METHODS AND RESULTS: Four hundred seven patients with suspected AMI admitted within 24 hours of symptoms onset were enrolled. In a ratio of 2:1, 268 patients were allocated to receive GIK (high- or low-dose) and 139 to receive control. Phlebitis and serum changes in the plasma concentration of glucose or potassium were observed more often with GIK. A trend toward a nonsignificant reduction in major and minor in-hospital events was observed in patients allocated to GIK. In 252 patients (61.9%) treated with reperfusion strategies, a statistically significant reduction in mortality (relative risk [RR] 0.34; 95% CI: 0.15 to 0.78; 2P=0.008) and a consistent trend toward fewer in-hospital events in the GIK group were observed. CONCLUSIONS: Our results confirm that a metabolic modulation strategy in the first hours of an AMI is feasible, applicable worldwide, and has mild side effects. The statistically significant mortality reduction in patients who underwent a reperfusion strategy might have important implications for the management of AMI patients. It is now essential to perform a large-scale trial to reliably determine the magnitude of benefit.     

Reporting of gender-related information in clinical trials of drug therapy for myocardial infarction

The genomic RNA of Hepatitis A virus (HAV), a picornavirus of the hepatovirus group, is a single-stranded molecule, ca. 7.5 kb in length of positive polarity. Translation of this uncapped RNA starts at the 10th (or 11th) AUG triplet (position 734-36), by a mechanism of internal initiation of translation. The long sequences extending between the uncapped 5'-end and the translation initiation site contain two (instead of just one) pyrimidine-rich tracts (PRTs) spanning nucleotides 94-140 and 711-724, respectively. The latter lies only 11 nucleotides upstream from the initiation site of translation, and the question arose as to whether the notoriously poor replication ability of HAV was a consequence of a down regulation of translation due to the too short "spacer" sequence intervening between the 3'-PRT and the initiation of the main open reading frame. To address this issue, a series of full-length HAV cDNA clones were constructed in which the "spacer" sequence (normally 11 nts) was brought to 45 nts. Following transfection of COS-1 cells with these constructs, the amount of HAV (+)-strand RNA was determined by dot hybridization using a strand-specific RNA probe. HAV cDNA clones carrying a 45-nt "spacer" increased two-fold the rate of (+)-strand viral RNA synthesis, suggesting that the poor translation ability of HAV RNA may be one of the mechanisms responsible for the lengthy replication cycle of HAV.     

Atenolol use and clinical outcomes after thrombolysis for acute myocardial infarction: the GUSTO-I experience. Global Utilization of Streptokinase and TPA (alteplase) for Occluded Coronary Arteries

OBJECTIVES: We assessed the use and effects of acute intravenous and later oral atenolol treatment in a prospectively planned post hoc analysis of the GUSTO-I dataset. BACKGROUND: Early intravenous beta blockade is generally recommended after myocardial infarction, especially for patients with tachycardia and/or hypertension and those without heart failure. METHODS: Besides one of four thrombolytic strategies, patients without hypotension, bradycardia or signs of heart failure were to receive atenolol 5 mg intravenously as soon as possible, another 5 mg intravenously 10 min later and 50 to 100 mg orally daily during hospitalization. We compared the 30-day mortality of patients given no atenolol (n=10,073), any atenolol (n=30,771), any intravenous atenolol (n=18,200), only oral atenolol (n=12,545) and both intravenous and oral drug (n=16,406), after controlling for baseline differences and for early deaths (before oral atenolol could be given). RESULTS: Patients given any atenolol had a lower baseline risk than those not given atenolol. Adjusted 30-day mortality was significantly lower in atenolol-treated patients, but patients treated with intravenous and oral atenolol treatment vs. oral treatment alone were more likely to die (odds ratio, 1.3; 95% confidence interval, 1.0 to 1.5; p=0.02). Subgroups had similar rates of stroke, intracranial hemorrhage and reinfarction, but intravenous atenolol use was associated with more heart failure, shock, recurrent ischemia and pacemaker use than oral atenolol use. CONCLUSIONS: Although atenolol appears to improve outcomes after thrombolysis for myocardial infarction, early intravenous atenolol seems of limited value. The best approach for most patients may be to begin oral atenolol once stable.     

Dynamic vectorcardiography for early diagnosis of acute myocardial infarction compared with 12-lead electrocardiogram. BIOMACS Study Group

BACKGROUND: The aim of the study was to assess the diagnostic accuracy of multilead continuous vectorcardiography (VCG) for early diagnosis of acute myocardial infarction (AMI) in patients admitted to hospital because of suspicion of AMI. VCG was compared with resting 12-lead electrocardiogram (ECG) on admission. METHODS: In a multicentre study, 107 patients with chest pain (< or = 12 h) were included. The diagnosis of AMI was on the basis of World Health Organization criteria. Continuous VCG was recorded for 12-24 h and the data were evaluated blindly at 2 and 6 h of recording and after the completion of recording (12-24 h). RESULTS: AMI was diagnosed in 74 patients. The VCG recording had a diagnostic accuracy of 71% after 2 h and 86% after both the 6 h and the completed VCG recording. Compared with ECG on admission, the VCG recording after 6 h showed a significantly greater sensitivity: 86% compared with 62% (P < 0.01). In patients with non-diagnostic ECG on arrival (n = 55), VCG after 6 h had a diagnostic accuracy of 85%, a sensitivity of 82% and a specificity of 89%. CONCLUSIONS: VCG might be useful for early diagnosis of AMI, especially in patients with non-diagnostic ECG.     

Concomitant infarction of the right ventricle in patients with acute transmural myocardial infarction (author's transl)

In 56 patients with acute transmural myocardial infarction hemodynamic parameters were studied. 21 patients proved to suffer from anterior infarction and 35 patients an inferior infarction. By clinical as well as by hemodynamic findings 10 patients out of the group of the 35 patients with inferior infarction were suspect of having a concomitant infarction of the right ventricle. As it is known from literature and documented by the present results this is not a rarity. Failure of the right ventricle is the main cause of death in these patients.     

Therapy of acute myocardial infarct (1994-1996) at non-university hospitals in Switzerland (CHAMI Study)

The CHAMI study (Confederatio Helvetica Acute Myocardial Infarction) recorded the therapies administered for acute myocardial infarction in 520 consecutive patients between October 1994 and February 1996 at 10 non-academic hospitals in Switzerland. The patients in this group consisted of 363 men and 157 women with an average age of 63.2 years. The prescribed medications administered from the day of hospital admission until the day of discharge were recorded. In the acute phase, the patients were given the following therapy: thrombolytic agents 40%, i.v. nitrates 65%, i.v. beta-blockers 22%, aspirin 95%, oral beta-blockers 36%, ACE inhibitors 14%. Impressive was the lower distribution of thrombolytic agents and beta-blockers among the older patients (age > 70) (thrombolytic agents 52.1% vs 28.4%; oral beta-blockers 44.0% vs 29.1%) and in particular among women (thrombolytic agents 26.8% vs 46%; oral beta-blockers 29.3% vs 39.7%) in men. Therapy at hospital discharge consisted, inter alia, of aspirin (73%), beta-blockers (54%), ACE inhibitors (3%), and lipid lowering agents (10%). The hospital mortality was 12.6%. The CHAMI study provided the participating hospitals with a quality control comparison with other participating centers and impressively demonstrated with the example of the lipid lowering agents, that the significance of secondary prophylaxis is assigned too little importance in contrast to acute therapy.     

The antiarrhythmic effects of verapamil in acute myocardial infarction. Considerations on the possible action mechanism (author's transl)

In 12 patients affected by acute myocardial infarction complicated only by ventricular extrasystoles, verapamil was highly effective in the control of the arrhythmias. This result is in agreement with the experimental finding that ischemia inactivates partially or totally early Na+ inward currents, so that fast fibers become slow fibers. The efficacy of verapamil stresses the importance of these fibers which have acquired a slow response in the genesis of arrhythmias due to acute coronary attacks and opens interesting therapeutical prospects.     

Intravenous diltiazem in acute myocardial infarction. Diltiazem as adjunctive therapy to activase (DATA) trial

OBJECTIVES: This study was defined as a pilot investigation of the usefulness and safety of intravenous diltiazem as adjunctive therapy to tissue plasminogen activator in acute myocardial infarction, followed by oral therapy for 4 weeks. BACKGROUND: Experimental studies have documented that calcium antagonists protect the myocardial cell against the damage caused by coronary artery occlusion and reperfusion, yet no benefits have been conclusively demonstrated in acute myocardial infarction (AMI) in humans. METHODS: In this pilot study, 59 patients with an AMI treated with tissue-type plasminogen activator (t-PA) were randomized, double blinded, to intravenous diltiazem or placebo for 48 h, followed by oral therapy for 4 weeks. The primary objective was to detect an effect on indices of regional left ventricular function and perfusion. Patients were also closely monitored for clinical events, coronary artery patency and indices of infarct size and of left ventricular function. RESULTS: Creatine kinase elevation, Q wave score, global and regional left ventricular function and coronary artery patency at 48 h were not significantly different between the diltiazem and placebo groups. A greater improvement observed in regional perfusion and function with diltiazem was likely explained by initial larger defects. Diltiazem, compared to placebo, reduced the rate of death, reinfarction or recurrent ischemia at 35 days from 41% to 13% (p=0.027) and prevented the need for an urgent intervention. The rate of death or myocardial infarction was reduced by 65% (p=0.15). These benefits could not be explained by differences in baseline characteristics such as age, site and extent of infarction, time of inclusion or concomitant therapy. Heart rate and blood pressure were reduced throughout the study with active diltiazem treatment. Side effects of diltiazem were bradycardia and hypotension that required transient or permanent discontinuation of the study drug in 27% of patients, vs. 17% of patients with placebo. CONCLUSIONS: A protective effect for clinical events related to early postinfarction ischemia and reinfarction was suggested in this study, with diltiazem administered intravenously with t-PA followed by oral therapy for 1 month, with no effect on coronary artery patency and left ventricular function and perfusion.     

Cardiac event rates after acute myocardial infarction in patients treated with verapamil and trandolapril versus trandolapril alone. Danish Verapamil Infarction Trial (DAVIT) Study Group

Angiotensin-converting enzyme (ACE) inhibitors improve survival in patients with congestive heart failure (CHF) after an acute myocardial infarction (AMI), but mortality may be as high as 10% to 15% after 1 year. Verapamil prevents cardiac events after an AMI in patients without CHF. We hypothesized that in postinfarct patients with CHF already prescribed diuretics and an ACE inhibitor, additional treatment with verapamil may reduce cardiac event rate. In this multicenter, double-blind study, patients with CHF receiving diuretic treatment were consecutively randomized to treatment with trandolapril 1 mg/day for 1 month and 2 mg/day the following 2 months (n = 49), or to trandolapril as mentioned plus verapamil 240 mg/day for 1 month and 360 mg/day for 2 months (n = 51). Trial medication started 3 to 10 days after AMI. All patients were followed for 3 months. End points in the trandolapril/trandolapril-verapamil groups were death 1/1, reinfarction 7/1, unstable angina 9/3, and readmission for CHF 6/2. The 3-month first cardiac event rate was 35% in trandolapril-treated patients and 14% in trandolapril-verapamil-treated patients (hazard ratio 0.35, 95% confidence interval 0.15 to 0.85, p = 0.015). These data suggest that verapamil reduces cardiac event rates in post-AMI patients with CHF when added to an ACE inhibitor and a diuretic.     

Acute myocardial infarction. Experiences of the referral network of the Beaujon and Bichat hospitals (with the collaboration of the Emergency Medical and Resuscitation Service of Beaujon)

OBJECTIVES: Hospital management of acute myocardial infarction raises many problems in terms of medical care and organization, especially concerning the use or not of emergency corongraphy and angiography. We assessed the pertinence and consequences of a referral network operating between two cardiology units at the Beaujon and Bichat hospitals in Paris. All interventional procedures were performed at the Bichat unit. Prehospital emergency care units were integrated into the exprience and informed of indications for first line coronarography. METHODS: All cases of myocardial infarction admitted within 6 hours to the two units between 1993 to 1996 were analyzed and compared. RESULTS: Indications for referral from Beaujon to Bichat for emergency coronarography and possible angioplasy declined from 21% in 1993 to 10% in 1996. This decline was particularly noteworthy for first intention indications suggesting improved prehospital selection since the number of cases of acute myocardial infarction admitted to Beaujon remained unchanged. Certain patient characteristics differed between the two units: age (68.4 +/- 12.9 years at Beaujon versus 60.5 +/- 13.6 years at Bichat in 1996, p < 0.01) and reperfusion attempts (73% versus 90% in 1996 respectively, p < 0.01). The rate of fatal and non-fatal events were not different: 40 and 40% at Beaujon and 38 and 28% at Bichat in 1993 and 1996 respectively. CONCLUSION: These findings demonstrate that a management network can operate effectively between two hospital cardiology units and emergency care structures, allowing better patient selection for emergency coronography and possible angioplasty.     

Factor V (Arg 506-->Gln) mutation in young survivors of myocardial infarction

Many young patients with venous thromboembolic disease are partially resistant to the anticoagulant action of activated protein C as a result of factor V (Arg 506 --> Gln) mutation. The frequency of this mutation in young patients with arterial thrombotic diseases, such as myocardial infarction, is less well established. We studied 100 young patients with myocardial infarction and 100 age- and sex-matched controls. One patient (1%; 95% CL 0.05-6.2) and two controls (2%; 95% CL 0.3-7.7) were heterozygotes for the mutation; there was no homozygote in either group. Hence, premature myocardial infarction is not associated with heterozygosity for factor V (Arg 506 --> Gln) mutation.     

Intervention with PTCA and CABG following thrombolysis for acute myocardial infarction. Australian data from GUSTO 1 (1991-3) and International Study Group r-TPA-Streptokinase Mortality (1989) trials. Global Utilisation of Streptokinase and Tissue

Genotoxic stress triggers signalling pathways that either mediate cell killing or protection of affected cells. While induction of p53 is observed for most of the genotoxins, activation of MAPK/SAPK cascades is not a general response. The role of MAPK/SAPK activation on cell fate, seems to be dependent, in some systems, on the balanced response among both cascades. We have here examined the effect of cis and trans-DDP on the activation of ERK and JNK activities. While no significant induction of ERK was observed with the compounds, both of them are able to strongly activate JNK. Trans-DDP response is rapid and transient while the cis-DDP one is slow and persistent. In contrast with the observed nuclear translocation of JNK in response to U.V. light, none of the platinum compounds induces translocation, on the contrary, activation of JNK occurs in both the nuclear and cytoplasmic compartments. Inhibition of tyrosine phosphatases by orthovanadate pretreatment prolongs the time of JNK induction in response to both platinum compounds. The positive modulation of JNK activation correlates with an increase in toxicity that, for cis-DDP corresponds to a tenfold decrease in the IC50. A strong increase in MKP-1 levels was observed only in response to trans-DDP suggesting the involvement of this activity in the downregulation of JNK activity in response to this compound. Altogether the results suggest that the prolonged activation of JNK in response to cis-DDP contributes to cell death induction.