J. Herre Kingma

THE VALUE OF CLASS IC ANTIARRHYTHMIC DRUGS FOR ACUTE CONVERSION OF PAROXYSMAL ATRIAL FIBRILLATION OR FLUTTER TO SINUS RHYTHM

In a single-blind randomized study, the efficacy and safety of intravenous propafenone (2 mg/kg body weight per 10 min) versus flecainide (2 mg/kg per 10 min) were assessed in 50 patients with atrial fibrillation or flutter. Treatment was considered successful if sinus rhythm occurred within 1 h. Conversion to sinus was achieved in 11 (55%) of 20 patients with atrial fibrillation treated with propafenone and in 18 (90%) of 20 with atrial fibrillation treated with flecainide (p less than 0.02). If atrial fibrillation was present less than or equal to 24 h, conversion to sinus rhythm was achieved in 8 (57%) of 14 patients in the propafenone group and 13 (93%) of 14 in the flecainide group (p less than 0.05). Atrial flutter was converted in two (40%) of five patients treated with propafenone and in one (20%) of five with flecainide (p = NS). Mean time to conversion was 16 +/- 10 min in the propafenone group versus 18 +/- 13 min in the flecainide group (p = NS). QRS lengthening (83 +/- 15 to 99 +/- 20 ms) was observed only in the patients treated with flecainide (p less than 0.001). Patients successfully treated with propafenone showed significantly higher plasma levels than those whose arrhythmia did not convert to sinus rhythm. Transient adverse effects were more frequent in the flecainide group (40%) than in the propafenone group (8%) (p less than 0.01). In conclusion, at a dose of 2 mg/kg in 10 min, flecainide is more effective than propafenone for conversion of paroxysmal atrial fibrillation to sinus rhythm. However, considering the propafenone plasma levels and very few adverse effects, the dose or infusion rate, or both, used in the propafenone group may not have been sufficient to achieve an optimal effect. Neither drug seems very effective in patients with atrial flutter.

Intravenous Flecainide Versus Verapamil for Acute Conversion of Paroxysmal Atrial Fibrillation or Flutter to Sinus Rhythm

In a single-blind randomized study, the efficacy of intravenous flecainide (2 mg/kg/10 minutes) versus verapamil (10 mg/1 minute) was assessed in 40 patients with paroxysmal atrial fibrillation (AF) or atrial flutter (AFI). The treatment was considered successful if sinus rhythm occurred within 1 hour. Of 20 patients receiving flecainide, 14 of 17 (82%) with AF converted to sinus rhythm, but in 3 patients with AFI flecainide failed. All patients treated with verapamil (17 AF, 3 AFI) showed lower ventricular rates after 1 hour; however, only 1 (6%) with AF converted to sinus rhythm and 1 (6%) converted to AFI. Patients who did not convert to sinus rhythm after treatment with verapamil were treated with flecainide and observed for another hour. After the change to flecainide, 9 of 15 patients (60%) with AF still converted. Thus, 23 of 32 patients (72%) with AF and none of 7 with AFI converted to sinus rhythm after treatment with flecainide. Conversion to sinus rhythm was achieved in 19 of 22 patients (86%) when AF lasted less than 24 hours and in 4 of 10 (40%) when the arrhythmia lasted greater than 24 hours. Transient adverse effects were noted in 10 patients (26%) after flecainide. In summary, flecainide is an effective and safe drug for conversion of paroxysmal AF to sinus rhythm, but ineffective for AFI. Verapamil appears to be of no use for conversion of AF or AFI to sinus rhythm.

Effects of Quinapril on Clinical Outcome After Coronary Artery Bypass Grafting (The QUO VADIS Study)

The QUO VADIS study was designed to explore whether 1 year of angiotensin-converting enzyme inhibition with quinapril (40 mg/day) would decrease ischemia in patients who underwent coronary artery bypass grafting (CABG). Patients (n = 149) scheduled for CABG were randomized 4 weeks before surgery. Study medication was used from randomization up to 1 year after CABG. Exercise testing was performed at randomization; the exercise test was repeated 1 year after CABG and patients underwent 48-hour Holter monitoring. Clinical ischemic events were recorded and defined as death, revascularization, myocardial infarction, recurrence of angina pectoris, ischemic stroke, or transient ischemic attack. Baseline characteristics were similar between groups. Total exercise time increased overall by 75 +/- 76 seconds 1 year after CABG (placebo +79 +/- 75 seconds, quinapril +72 +/- 79 seconds, p = 0.6). All patients had ischemic ST-segment changes at randomization; 33% of patients had ischemic ST-segment changes 1 year after CABG (placebo 29%, quinapril 37%, p = 0.4). On Holter monitoring, the number of patients experiencing > or = 1 episodes of ischemia was equal in both groups. Treatment with quinapril significantly reduced clinical ischemic events after CABG: 15% in patients on placebo versus 4% of patients on quinapril (hazard ratio 0.23, 95% confidence interval 0.06 to 0.87, p = 0.02). Long-term quinapril treatment significantly reduced clinical ischemic events within 1 year after CABG, although ischemia at exercise testing and Holter monitoring was unchanged.

Deletion-type allele of the angiotensin-converting enzyme gene is associated with progressive ventricular dilation after anterior myocardial infarction

OBJECTIVES This study sought to determine whether patients who are homozygous for the deletion (D)-type allele of the angiotensin-converting enzyme gene display augmented ventricular dilation after myocardial infarction. BACKGROUND Recent evidence suggests that the deletion-type allele of the angiotensin-converting enzyme gene (DD genotype) is associated with an increased prevalence of myocardial infarction and myocardial hypertrophy. However, it is unknown whether the DD genotype is associated with adverse cardiac remodeling. To address this question we determined the genotype in patients enrolled in the Captopril and Thrombolysis Study (CATS), a prospective trial in which patients received either captopril or placebo during and after thrombolysis for a first anterior myocardial infarction. METHODS Cardiac volume was determined by echocardiography immediately after thrombolysis and at 1-year follow-up. The genotype for the angiotensin-converting enzyme was determined in 96 patients. Norepinephrine levels were assessed during and immediately after thrombolysis. RESULTS Immediately after thrombolysis, cardiac volume did not differ between genotype groups. However, at 1-year follow-up, both end-systolic and end-diastolic left ventricular volumes were significantly greater in the DD-genotype group. Norepinephrine increased to higher levels in the DD-genotype group that received placebo therapy. Captopril treatment effectively blunted both the norepinephrine increase and cardiac dilation in the DD-genotype group. CONCLUSIONS This exploratory study suggests that homozygosity for the angiotensin-converting enzyme deletion-type allele is associated with augmented neurohumoral activation as well as augmented cardiac dilation after an acute anterior myocardial infarction, an effect that may be susceptible to angiotensin-converting enzyme inhibition.

Which patient benefits from early angiotensin-converting enzyme inhibition after myocardial infarction? Results of one-year serial echocardiographic follow-up from the captopril and thrombolysis study (CATS)

OBJECTIVES In this study we sought to investigate the effect of intervention with captopril within 6 h of the onset of myocardial infarction on left ventricular volume and clinical symptoms of heart failure in relation to infarct size during a 1-year follow-up period. BACKGROUND Remodeling of the heart starts in the early phase of myocardial infarction and is associated with an adverse prognosis. Angiotensin-converting enzyme inhibition started in the subacute or late phase after myocardial infarction has been shown to improve prognosis. METHODS In the Captopril and Thrombolysis Study, 298 patients with a first anterior myocardial infarction treated with intravenous streptokinase were randomized to receive either oral captopril (25 mg three times a day) or placebo. The left ventricular volume index was assessed by two-dimensional echocardiography within 24 h, on days 3, 10 and 90 and after 1 year. RESULTS A small but significant increase in left ventricular volume indexes was observed after 12 months. Using a random coefficient model, no significant treatment effect on left ventricular volumes could be detected. In contrast, when survival models were used, the occurrence of left ventricular dilation was significatnly lower in captopril-treated patients (p = 0.018). In addition, the incidence of heart failure was lower in the captopril group (p < 0.03). This effect appeared early and was most obvious in patients with a medium-sized infarct (p = 0.04) and was not present in large infarcts. CONCLUSIONS Very early treatment with captopril after myocardial infarction significantly reduces the occurrence of early dilation and the progression to heart failure. These data underscore the importance of early treatment. Furthermore, patients with intermediate infarct size benefit the most from this treatment strategy.

Acute pharmacologic conversion of atrial fibrillation and flutter: the role of flecainide, propafenone, and verapamil.

Efficacy and safety of intravenous flecainide (2 mg/kg body weight in 10 minutes), verapamil (10 mg in 1 minute), and propafenone (2 mg/kg body weight in 10 minutes) were investigated in 90 consecutive patients with atrial fibrillation (AF) or flutter (AFL). In the first 40 patients, flecainide and verapamil were evaluated; in the second 50 patients, flecainide and propafenone were compared, both in a single-blind randomized study design. The primary end point was sinus rhythm occurring within 1 hour after start of infusion. Sinus rhythm was attained in 32 of 37 patients (86%) with AF treated with flecainide and in 11 of 20 patients (55%) with AF treated with propafenone. In recent onset AF (less than or equal to 24 hours) conversion rates were 24 of 25 patients (96%) in the flecainide group and 8 of 14 patients (57%) in the propafenone group (p less than 0.05). Conversion of AFL occurred in only 1 of 8 patients (13%) in the flecainide-treated patients and in 2 of 5 patients (40%) treated with propafenone (difference not significant). Verapamil was almost ineffective, since only 1 of 20 patients (5%) responded within 1 hour. Time to conversion was 21 +/- 17 minutes in the flecainide group and 16 +/- 10 minutes in the propafenone group. QRS widening occurred in flecainide-treated patients (83 +/- 15 to 99 +/- 20 msec; p less than 0.001), but not after propafenone (83 +/- 11 to 86 +/- 12 msec). Significantly higher plasma levels were found in patients with conversion within 1 hour using propafenone.(ABSTRACT TRUNCATED AT 250 WORDS)

CAPTOPRIL REDUCES PURINE LOSS AND REPERFUSION ARRHYTHMIAS IN THE RAT-HEART AFTER CORONARY-ARTERY OCCLUSION

Captopril was perfused through isolated rat hearts; its effects after local ischemia and reperfusion were assessed. Upon reperfusion all untreated (10 out of 10) but only 4 (out of 10) captopril-treated (80 micrograms/ml) hearts fibrillated (P less than 0.02). Purine overflow increased upon reperfusion but was reduced by captopril (597 +/- 62 and 333 +/- 41 nmol/min gdwt respectively; P less than 0.05). The pressure-rate index and the apex displacement were severely impaired after 30 min of reperfusion (32 +/- 16 and 10 +/- 5% respectively of initial values) but captopril reduced the injury of mechanical function (60 +/- 8; P less than 0.05 and 61 +/- 11; P less than 0.05 respectively). These results show that captopril reduces ventricular fibrillation and the loss of high energy phosphate nucleotides and thereby partly maintains mechanical function impaired by ischemia and reperfusion.

Efficacy and safety of a new selective class III antiarrhythmic agent dofetilide in paroxysmal atrial fibrillation or atrial flutter

that regional LV dysfunction is not responsible for this nonspecificity. Our results differ from those of Breithardt et al,4 who detected late potentials in only 9% of patients with normal wall motion compared with 46% of patients with regional akinesia or dyskinesia. However, the recording methodology and semiqualitative criteria for diagnosing late potentials in their study differed markedly from those currently used by most investigators2,3 and used in our report’. In addition, the results differ primarily in the higher frequency of late potentials recorded in our control group, which also exceeds the frequency of an abnormal SAECG in normal subjects reported previously in several other studies.2,5,6 However, our “normal” patients had undergone cardiac catheterization and were much older than the normal subjects in those studies, which consisted of nurses and medical residents2 or other healthy volunteers who had not undergone cardiac catheterization.5,6 Increasing age has been found recently to independently increase the incidence of late potentials,7 and probably accounts for the frequency of late potentials in our control group. This finding of a reduced positive predictive value of the SAECG in older patients has important implic;ations for the prospective value of this test, because the question of susceptibility to VT is far more likely to be raised in older patients with suspected heart disease than it is in young, healthy people.

Electrophysiologic profile and efficacy of intravenous dofetilide (UK-68,798), a new class III antiarrhythmic drug, in patients with sustained monomorphic ventricular tachycardia☆

There is increasing evidence that class III antiarrhythmic agents may be superior to class I agents for the long-term treatment of life-threatening ventricular tachyarrhythmias. This open study evaluated the acute electrophysiologic effects, antiarrhythmic efficacy, and safety of different doses of intravenous dofetilide, a new class III drug, in 50 patients with sustained monomorphic ventricular tachycardia inducible by programmed electrical stimulation who had previously been unsuccessfully treated with 0 to 7 (median 3) other drugs. Intravenous dofetilide was administered over 60 minutes at the following dose levels: 1.5, 3.0, 6.0, 9.0, and 15.0 micrograms/kg. Significant class III activity was apparent at doses of 3.0 to 15.0 micrograms/kg, as evidenced by dose-related prolongation of the QTc interval by 13.4% to 14.2%, ventricular effective refractory period by 7.9% to 20.6%, and ventricular functional refractory period by 7.3% to 25.0%. The corresponding mean +/- SD plasma dofetilide concentrations ranged from 1.45 +/- 0.52 to 6.48 +/- 1.31 ng/ml. There was no evidence of reverse use-dependence. At these electrophysiologically active dose levels, intravenous dofetilide suppressed (complete response) or slowed (partial response) inducible ventricular tachycardia in 17 of 41 patients (41%) compared with 0 of 9 patients receiving only 1.5 micrograms/kg. The response rate was fairly uniform among the groups receiving 3.0, 6.0, 9.0, and 15.0 micrograms/kg. Intravenous dofetilide was hemodynamically well tolerated. Torsades de pointes (which was self-limiting) developed in only 1 patient, who was allocated to receive 15.0 micrograms/kg. There were no other proarrhythmic episodes or serious adverse effects. Further evaluation of the therapeutic potential of dofetilide in the management of life-threatening ventricular arrhythmias is justified.

Left ventricular wall motion score as an early predictor of left ventricular dilation and mortality after first anterior infarction treated with thrombolysis

Abstract To recognize patients prone to subsequent left ventricular dilation after the acute phase of a myocardial infarction treated with thrombolysis, we studied 233 patients with a first anterior infarction, treated with thrombolysis, with 2-dimensional echocardiography within 12 hours after admission and 3 months later. A wall motion score index (WMSI) and left ventricular volumes were assessed, and enzymatic infarct size was expressed as cumulative alphahydroxybutyrate dehydrogenase determined in the first 72 hours after infarction. Patients who died (17 of 233, 7%) after a mean follow-up of 517 days had a significantly higher acute WMSI (2.1 ± 0.3, mean ± SD) than those who survived (1.9 ± 0.4) (p = 0.006). With use of this cutoff value of 2 for WMSI, ventricles with an acute WMSI ≤2 (62%) showed no increase in end-diastolic volume index (EDVI) or end-systolic volume index (ESVI), whereas ventricles with an acute WMSI >2 (38%) showed a significant increase in ESVI (6.1 ± 12.2 ml/m 2 ) and in EDVI (10.3 ± 16.6 ml/m 2 ) in the first 3 months. Using a cutoff value of 1,000 U/L for cumulative alphahydroxybutyrate dehydrogenase, only infarcts with a value of > 1,000 U/L (52%) caused a significant increase in EDVI (10.8 ± 14.3 ml/m 2 ) and ESVI (6.5 ± 10.0 ml/m 2 ) in the first 3 months. Thus, acutely assessed WMSI of >2 can readily predict subsequent dilation in patients with a first anterior infarction treated with streptokinase and is a good predictor of mortality. Enzymatic infarct size also is a good predictor of dilation, although not available until 3 days after infarction.