Joan R. Lutz

A Randomized Trial of Intracoronary Streptokinase in the Treatment of Acute Myocardial Infarction

Fifty patients with acute myocardial infarction were randomly assigned to receive either intracoronary streptokinase or standard (control) therapy within about three hours after the onset of pain. Coronary perfusion was reestablished in 19 of 24 patients receiving streptokinase. Streptokinase alleviated pain (as indicated by differences in subsequent morphine use). The Killip class was significantly improved after therapy with streptokinase, as were changes in radionuclide ejection fraction between Days 1 and 10 in surviving patients (+3.9 vs. -3.0 per cent, P less than 0.01). The echocardiographic wall-motion index also showed greater improvement after streptokinase treatment (P less than 0.01). Streptokinase therapy was associated with rapid evolution of electrocardiographic changes, which were essentially complete within three hours after therapy, but loss of R waves, ST elevation, and development of Q waves in the convalescent period were greater in the control group (P less than 0.01). The time required to reach peak plasma enzyme concentrations was significantly shorter after streptokinase. The incidence of early and late ventricular arrhythmias was not affected by treatment. We conclude that intracoronary streptokinase appears to have a beneficial effect on the early course of acute myocardial infarction.

A randomized trial of low-dose beta-blockade therapy for idiopathic dilated cardiomyopathy

Beta-blockade therapy to improve survival in idiopathic dilated cardiomyopathy (IDC) has been both advocated and criticized. However, randomized studies have not been performed. Thus, 50 patients with IDC were randomized in pairs to standard therapy (C) alone or with beta blockade (BB). Beta-blockade therapy with metoprolol was titrated from 12.5 to 50 mg twice daily as tolerated (final average dose, 61 mg/day). Groups were comparable in age (C, 50 +/- 15 years; BB, 51 +/- 13 years), gender (C, 76% male; BB, 56% male), entry functional class (C, 2.8 +/- 0.8; BB, 2.7 +/- 0.7), and left ventricular ejection fraction (C, 27 +/- 12%; BB, 29 +/- 10%). Follow-up averaged 19 months (range 1 to 38). One subject in each group was lost to follow-up. There were 3 early BB dropouts (within 2 days) due to low-output syndrome (2 patients) or fatigue (1 patient). Eleven patients died. By intention to treat, 5 BB and 6 C patients died (difference not significant). By actual treatment, 3 BB patients died, including 2 late dropouts (at 0.2, 10 and 17 months), and 8 C patients died (at 2, 9, 9, 15, 18, 24, 29 and 32 months, p = 0.12). In additional, functional evaluation on follow-up (functional class, San Diego questionnaire and exercise time) all tended to favor those receiving BB. Low-dose BB is tolerated in 80% of IDC patients on a long-term basis. Those continuing to take BB have a good prognosis. Mortality in C patients, however, is less than in some retrospective studies.(ABSTRACT TRUNCATED AT 250 WORDS)

A randomized trial of intravenous and intracoronary streptokinase in patients with acute myocardial infarction.

The clinical effects of intravenous streptokinase in patients with acute myocardial infarction were compared with those of intracoronary streptokinase in a randomized, prospective study. Comparisons were also made with a historical control group. Fifty patients were entered into the study at 2.4 +/- 1.2 hr after onset of pain, and 27 were assigned to intravenous and 23 to intracoronary therapy. The doses of streptokinase averaged 212,000 U ic and 845,000 U iv (0.75 X 10(6) U/5 hr, n = 14 or 10(6) U/1 hr, n = 13). Results of studies of the two intravenous dosage schedules were similar and so were combined. Streptokinase was administered at 2.8 +/- 1.0 hr after onset of pain in the intravenous and at 4.3 +/- 1.4 hr in the intracoronary drug group (p less than .001). Convalescent (day 10) radionuclide ejection fractions were 54 +/- 14% for the intravenous and 50 +/- 16% for the intracoronary drug group. Change in ejection fraction from day 1 to 10 tended to be greater after intravenous drug: 5.1% (p less than .08) vs 1.2% (NS). Semiquantitative regional wall motion indexes in the infarct zone showed significant and similar modest improvement from admission to day 10 in both groups (p less than .02). Accelerated enzyme-release kinetics were noted after both therapies. Times of peak enzyme levels for patients on intravenous and intracoronary drug were, respectively, 12.5 +/- 5.0 and 11.5 +/- 4.3 hr for creatine kinase MB isoenzyme and 31.7 +/- 11.8 and 28.1 +/- 12.7 hr for lactic dehydrogenase (LDH). Peak LDH-1 level was lower in patients receiving intravenous drug than in the historical control group (p less than .05). Electrocardiographically summed ST segments diminished rapidly after therapy in both groups; Q wave development was similar and overall R wave loss was equivalent and less extensive compared with in historical control subjects. Infarct pain requiring morphine was diminished similarly in both treatment groups. Incidence of early arrhythmias and heart failure also did not differ. Posttherapy ischemic events and early surgery tended to be more common in the intracoronary group and bleeding was more common in the intravenous group. Intravenous drug did not decrease early hospital mortality (intravenous drug = 5, historical control = 4, intracoronary drug = 1); the differences in this parameter among groups were not significant. At convalescent angiographic evaluation, anterograde perfusion was present in 73% of those receiving intravenous and 76% of those receiving intracoronary drug.(ABSTRACT TRUNCATED AT 400 WORDS)

Electrophysiologic and antiarrhythmic effects of oral flecainide in patients with inducible ventricular tachycardia

Flecainide has demonstrated unsurpassed antiarrhythmic activity in patients with stable ventricular arrhythmias, but its effects in those with ventricular tachycardia or fibrillation have not been evaluated. Electrophysiologic and hospital evaluation of oral flecainide therapy (150 to 200 mg every 12 hours for 4 to 6 days) was performed in 15 patients with clinically documented ventricular tachyarrhythmias treated unsuccessfully with an average of 3.7 (range 1 to 10) antiarrhythmic drugs. Plasma flecainide concentrations averaged 769 ng/ml (range 377 to 1,152). Cardiac conduction times increased; AH interval changed by + 29%, HV interval by +42%, PR interval by +25%, QRS duration by +14% (all p Outpatient experience in 10 patients has been generally concordant with in-hospital evaluation at a median of 6.5 months. Flecainide has been well tolerated. Unexpected arrhythmias have included exercise-initiated tachycardia in one patient and slow, hemodynamically stable tachycardia (110 beats/min) in another patient. Oral flecainide is an important antiarrhythmic agent for the management of inducible ventricular tachyarrhythmias. Cardiac conduction times and ventricular refractoriness increase; favorable responses to programmed stimulation are frequent and generally predict outpatient safety and efficacy.

Occurrence of ventricular arrhythmias in patients receiving acute and chronic infusions of milrinone

Milrinone is a promising new inotrope, but its arrhythmogenic potential has not been defined. We monitored ventricular arrhythmias during a 24-hour baseline and 48-hour milrinone infusion period in 12 patients with chronic heart failure. Patients were characterized by a mean age of 58 years and a left ventricular ejection fraction of 21%. Nine (75%) were male, nine had primary idiopathic dilated cardiomyopathy, and three had coronary artery disease. None had a history of cardiac arrest or sustained ventricular tachyarrhythmia. Milrinone was given as a loading dose (mean 53 micrograms/kg/10 min; range 37.5 to 75) followed by a 48-hour maintenance infusion (mean 0.53 micrograms/kg/min; range 0.25 to 0.75). Acutely, cardiac index increased by 27% and pulmonary wedge pressure decreased by 30% during milrinone; changes were maintained during continued therapy. Ventricular arrhythmia response was variable, with no significant overall difference. However, a trend toward increased ectopic activity was noted. No sustained tachyarrhythmias occurred. Mean frequency of premature ventricular complexes (PVCs) was 87 +/- 48 PVCs/hr (x +/- SEM) during baseline monitoring and 141 +/- 69/hr following infusion of the drug (p = 0.08). Mean frequency of couplets was 6.0 +/- 4.9/hr before drug infusion and 14.3 +/- 11.0/hr during infusion (p = 0.21). Mean frequency of runs was 0.9 +/- 0.8/hr before and 2.7 +/- 2.4/hr during drug infusion (p = 0.29). Two patients met criteria for proarrhythmia (increased PVCs of greater than 4x and/or repetitive forms of greater than 10x. However, neither proarrhythmia patient required reduction in the dosage of milrinone or additional antiarrhythmic therapy.(ABSTRACT TRUNCATED AT 250 WORDS)

HLA A, B and DR typing in idiopathic dilated cardiomyopathy: a search for immune response factors

Several autoimmune diseases have been associated with increased frequencies of various histocompatibility antigen (HLA) types that may be linked to immune response genes. Idiopathic dilated cardiomyopathy (IDC) has been proposed as a disease with autoimmune features, but HLA associations have not been evaluated. We performed HLA typing in 37 consecutive patients with IDC. Patients with habitual alcoholism were excluded. Results showed that no single HLA type could account for most cases; IDC is a genetically heterogeneous disease. However, uneven distributions were noted for certain types. Haplotype frequency of B27 was 0.145 in patients vs 0.033 in 5,726 local control subjects (p less than 0.001). Other A and B frequencies (except A2) were evenly distributed. HLA DR typing also revealed differences. The DR4 locus was present in 54% (19 of 35) of patients, vs 32% (26 of 82) of blood bank control subjects (p less than 0.02). The associated relative risk of DR4 was 2.2 and the etiologic fraction 0.29. Sex, disease chronicity, functional class, ejection fraction and biopsy evidence of myocarditis did not distinguish DR4-positive from DR4-negative patients, but they were older (54 +/- 12 vs 42 +/- 14 years, p less than 0.02). Of note, 68% were positive for DR4 or B27, or both. HLA DR6Y was underrepresented; it was present in 9% (3 of 35) of patients, vs 26% (21 of 82) of control subjects (p less than 0.04). The relative risk of DR6Y was 0.27 and the preventive fraction 0.19. These associations will require independent confirmation. However, they suggest that genetically determined immune response factors associated with HLA loci may play a role in pathogenesis in certain patients with IDC.

Pirmenol for control of ventricular arrhythmias: Oral dose-ranging and short-term maintenance study

The antiarrhythmic efficacy and safety of oral pirmenol hydrochloride were assessed during a controlled, dose-ranging and short-term maintenance study in 12 patients with frequent (greater than 480/8 hours) premature ventricular complexes (PVCs). Eleven patients (92%) responded favorably (greater than 70% PVC suppression) to a trial of different doses. Mean interval (8-hour) suppression of PVC frequency was 95% in these 11 and 86% in the entire group. Twenty-four-hour suppression was similar in responders (88%). Repetitive PVCs were essentially eliminated. The mean effective dose was 316 mg/day (105 mg/8 hours). The average predose (trough) plasma concentration at the end of dose ranging was 1.4 micrograms/ml and the drug elimination half-life 7.3 hours (n = 12). Of 11 responding patients, 10 completed a 2-week outpatient trial. Pirmenol continued to be effective and tolerated in 8 patients, maintaining an overall average outpatient PVC suppression of 80%. The electrocardiographic intervals were mildly prolonged after multiple dosing (PR + 7%, QRS + 12%, QTc + 8%; all p less than 0.01). Blood pressure and heart rate did not change during treatment. The echocardiographic ejection fraction was maintained. Thus, oral pirmenol appears to be effective, conveniently administered and well tolerated as an antiarrhythmic agent for control of ventricular extrasystoles.

Long-term follow-up after intracoronary streptokinase for myocardial infarction: A randomized, controlled study

Intracoronary streptokinase (SK) may have beneficial effects on the in-hospital course of acute myocardial infarction (MI), but long-term outcome is unknown. We evaluated the outpatient course of 50 MI patients, randomly treated with either SK (n = 24) or standard therapy (n = 26), who presented within 2.7 +/- 0.7 hours of symptoms. Coronary reperfusion occurred in 19 (79%) SK patients. Survivors were followed for a mean of 18.7 months (range 11 to 28.5); information was current in 48 patients (96%). Both groups received antiplatelet therapy for 3 months. A total of five deaths occurred in the control group and two in the SK group, including one posthospital death in each. Nonfatal MIs totaled five in control patients and three in SK patients, including five posthospital MIs (three control, one SK). Differences in major events (death or nonfatal MI) favoring SK did not quite reach statistical significance (10 control vs 5 SK). Bypass surgery was performed in seven SK and four control patients (NS). Angina occurred in more control (15) than SK (six) patients (p less than 0.01), and more control patients used long-acting nitrates (14 control, three SK; p less than 0.01). Palpitations were noted by nine control and one SK patient (p less than 0.01), and documented late arrhythmias were present in four control patients and no SK survivors (p less than 0.05). Symptoms suggestive of heart failure were present in seven control and one SK patient (p less than 0.01); two control patients were hospitalized for failure. Use of beta blockers, calcium channel blockers, and other cardiac medications did not differ.(ABSTRACT TRUNCATED AT 250 WORDS)

Initial and long-term outpatient experience with pirmenol for control of ventricular arrhythmias

SummaryPirmenol, a new class IA antiarrhythmic agent, has shown promise in short-term trials, but long-term efficacy has not been documented. We thus evaluated 11 patients with frequent (≥60/h) premature ventricular complexes (PVC) given oral pirmenol for 25–727 days. Ten of 11 patients entering the long-term open trial had shown ≥70% (mean 83%) PVC suppression during in-hospital pirmenol dose ranging. Long-term pirmenol was given in divided doses of 100–600 mg/day. Mean PVC frequency during baseline was 13,078/24h (range, 3,218–32,718); couplets averaged 481/24h (1–2,829) and runs 45/24h (0–334). Ambulatory monitoring was performed at 1, 3, 6, and 12 months, then semiannually. Mean absolute PVC suppression at 1 month averaged 75% (p≤0.02). Median individual percentage PVC suppression was 94%. During the first 3 months, 8 patients (73%) continued to show a favorable response (≥70% suppression), and 3 had arrhythmia recurrence and were dropped. One responder was withdrawn after the onset of paroxysmal atrial fibrillation, and another early responder was withdrawn after 3 months because of arrhythmia relapse. Six patients have been treated for over 1 year, with 99% mean PVC suppression. Mean couplet and run frequencies at 1 month decreased by means of 76% (p≤0.05) and 92% (p=0.001) respectively. At 1 year, couplets were suppressed 99.8% and runs by 99.7% in the 6 patients remaining on pirmenol. Mean QT interval increased slightly (7.1%,p<0.05); mean PR and QRS intervals were unchanged. Plasma pirmenol concentrations averaged 1.49 µg/ml at clinic evaluations, 1.72 µg/ml in responders vs 1.08 µg/ml in nonresponders. Inade-quate plasma drug concentrations may be one cause for arrhythmia recurrence. Adverse effects were minimal. Thus, oral pirmenol is a safe and effective agent for long-term outpatient management of complex ventricular arrhythmias in selected patients.

Comparison of intravenous lorcainide with lidocaine for acute therapy of complex ventricular arrhythmias: Results of a randomized study with crossover option

There is a need for effective, well tolerated, intravenous antiarrhythmic agents. The effects of lorcainide, a new class I antiarrhythmic agent, were compared with those of lidocaine in a randomized parallel study with cross-over option in 30 hospitalized patients with frequent (greater than 1/min) complex ventricular arrhythmias. Lorcainide loading dose was 2 mg/kg (at 2 mg/min) supplemented, if needed, with 100 mg in 1 hour; maintenance dose was 8 mg/h. Lidocaine loading dose was 1 mg/kg (at 25 mg/min) supplemented, if needed, with 50 mg in 2 minutes; maintenance dose was 2 or 3 mg/min (as needed). Arrhythmias were compared for 2 hours before and after drug loading. Initially responding patients (minimum of 70% arrhythmia suppression) were continued on maintenance therapy for 24 hours. Patients initially failing or with later arrhythmia escape crossed over to alternating therapy (seven to lidocaine, nine to lorcainide). The median frequency of premature ventricular complexes decreased by 76% after lidocaine (p less than 0.05) and by 93% after lorcainide (p less than 0.001); this difference approached significance (p = 0.06). More than 95% arrhythmia suppression was achieved by lorcainide in 47% of patients and by lidocaine in only 13% (p less than 0.05). Couplets decreased by a median of 100% after lorcainide and by 89% after lidocaine. Couplets were eliminated in 62% of the patients after lorcainide and in 27% after lidocaine (p = 0.06). There was 100% suppression of runs of premature beats in 11 patients after lorcainide and 99% suppression in 10 patients after lidocaine.(ABSTRACT TRUNCATED AT 250 WORDS)