Ross D. Fletcher

A Comparison of Enalapril with Hydralazine–Isosorbide Dinitrate in the Treatment of Chronic Congestive Heart Failure

BACKGROUND To define better the efficacy of vasodilator therapy in the treatment of chronic congestive heart failure, we compared the effects of hydralazine and isosorbide dinitrate with those of enalapril in 804 men receiving digoxin and diuretic therapy for heart failure. The patients were randomly assigned in a double-blind manner to receive 20 mg of enalapril daily or 300 mg of hydralazine plus 160 mg of isosorbide dinitrate daily. The latter regimen was identical to that used with a similar patient population in the effective-treatment arm of our previous Vasodilator-Heart Failure Trial. RESULTS Mortality after two years was significantly lower in the enalapril arm (18 percent) than in the hydralazine-isosorbide dinitrate arm (25 percent) (P = 0.016; reduction in mortality, 28.0 percent), and overall mortality tended to be lower (P = 0.08). The lower mortality in the enalapril arm was attributable to a reduction in the incidence of sudden death, and this beneficial effect was more prominent in patients with less severe symptoms (New York Heart Association class I or II). In contrast, body oxygen consumption at peak exercise was increased only by hydralazine-isosorbide dinitrate treatment (P less than 0.05), and left ventricular ejection fraction, which increased with both regimens during the 2 years after randomization, increased more (P less than 0.05) during the first 13 weeks in the hydralazine-isosorbide dinitrate group. CONCLUSIONS The similar two-year mortality in the hydralazine-isosorbide dinitrate arms in our previous Vasodilator-Heart Failure Trial (26 percent) and in the present trial (25 percent), as compared with that in the placebo arm in the previous trial, (34 percent) and the further survival benefit with enalapril in the present trial (18 percent) strengthen the conclusion that vasodilator therapy should be included in the standard treatment for heart failure. The different effects of the two regimens (enalapril and hydralazine-isosorbide dinitrate) on mortality and physiologic end points suggest that the profile of effects might be enhanced if the regimens were used in combination.

Effect of Vasodilator Therapy on Mortality in Chronic Congestive Heart Failure

To evaluate the effects of vasodilator therapy on mortality among patients with chronic congestive heart failure, we randomly assigned 642 men with impaired cardiac function and reduced exercise tolerance who were taking digoxin and a diuretic to receive additional double-blind treatment with placebo, prazosin (20 mg per day), or the combination of hydralazine (300 mg per day) and isosorbide dinitrate (160 mg per day). Follow-up averaged 2.3 years (range, 6 months to 5.7 years). Mortality over the entire follow-up period was lower in the group that received hydralazine and isosorbide dinitrate than in the placebo group. This difference was of borderline statistical significance. For mortality by two years, a major end point specified in the protocol, the risk reduction among patients treated with both hydralazine and isosorbide dinitrate was 34 percent (P less than 0.028). The cumulative mortality rates at two years were 25.6 percent in the hydralazine--isosorbide dinitrate group and 34.3 percent in the placebo group; at three years, the mortality rate was 36.2 percent versus 46.9 percent. The mortality-risk reduction in the group treated with hydralazine and isosorbide dinitrate was 36 percent by three years. The mortality in the prazosin group was similar to that in the placebo group. Left ventricular ejection fraction (measured sequentially) rose significantly at eight weeks and at one year in the group treated with hydralazine and isosorbide dinitrate but not in the placebo or prazosin groups. Our data suggest that the addition of hydralazine and isosorbide dinitrate to the therapeutic regimen of digoxin and diuretics in patients with chronic congestive heart failure can have a favorable effect on left ventricular function and mortality.

Amiodarone in Patients with Congestive Heart Failure and Asymptomatic Ventricular Arrhythmia

BACKGROUND Asymptomatic ventricular arrhythmias in patients with congestive heart failure are associated with increased rates of overall mortality and sudden death. Amiodarone is now used widely to prevent ventricular tachycardia and fibrillation. We conducted a trial to determine whether amiodarone can reduce overall mortality in patients with congestive heart failure and asymptomatic ventricular arrhythmias. METHODS We used a double-blind, placebo-controlled protocol in which 674 patients with symptoms of congestive heart failure, cardiac enlargement, 10 or more premature ventricular contractions per hour, and a left ventricular ejection fraction of 40 percent or less were randomly assigned to receive amiodarone (336 patients) or placebo (338 patients). The primary end point was overall mortality, and the median follow-up was 45 months (range, 0 to 54). RESULTS There was no significant difference in overall mortality between the two treatment groups (P = 0.6). The two-year actuarial survival rate was 69.4 percent (95 percent confidence interval, 64.2 to 74.6) for the patients in the amiodarone group and 70.8 percent (95 percent confidence interval, 65.7 to 75.9) for those in the placebo group. At two years, the rate of sudden death was 15 percent in the amiodarone group and 19 percent in the placebo group (P = 0.43). There was a trend toward a reduction in overall mortality among the patients with nonischemic cardiomyopathy who received amiodarone (P = 0.07). Amiodarone was significantly more effective in suppressing ventricular arrhythmias and increased the left ventricular ejection fraction by 42 percent at two years. CONCLUSIONS Although amiodarone was effective in suppressing ventricular arrhythmias and improving ventricular function, it did not reduce the incidence of sudden death or prolong survival among patients with heart failure, except for a trend toward reduced mortality among those with nonischemic cardiomyopathy.

Spontaneous Conversion and Maintenance of Sinus Rhythm by Amiodarone in Patients With Heart Failure and Atrial Fibrillation Observations from the Veterans Affairs Congestive Heart Failure Survival Trial of Antiarrhythmic Therapy (CHF-STAT)

BACKGROUND In a multicenter, double-blind, placebo-controlled study, the long-term effects of amiodarone on morbidity and mortality in patients with congestive heart failure (CHF) and atrial fibrillation (AF) were evaluated during a 4-year period. METHODS AND RESULTS Of 667 patients with CHF, 103 (15%) had AF at baseline. Of these, 51 were randomized to amiodarone and 52 to placebo. The group with sinus rhythm and the group in AF were comparable except for a higher proportion of AF in patients with nonischemic versus ischemic cardiomyopathy (41% versus 27%, P<0.005). The mean ventricular response (VR) during AF over 24 hours was reduced by amiodarone at 2 weeks (20%, P=0.001), at 6 months (18%, P=0.001), and at 12 months (16%, P=0.006). Maximal VR was reduced 22% (P=0.001) at 2 weeks, 19% (P=0.001) at 6 months, and 14% (P=0.001) at 12 months. Sixteen of 51 patients on amiodarone and 4 of 52 on placebo converted to sinus rhythm during the study (chi2=9.23, P=0.002). During follow-up, 11 of 268 patients in sinus rhythm on amiodarone at baseline and 22 of the 263 in sinus rhythm on placebo developed AF; the difference was significant (chi2=12.88, P=0.005). Analysis of total mortality during follow-up showed a significantly lower mortality rate (P=0. 04) in patients in AF at baseline who subsequently converted to sinus rhythm on amiodarone than in those who did not convert to sinus rhythm on the drug. CONCLUSIONS In patients with CHF, amiodarone has a significant potential to spontaneously convert patients in AF to sinus rhythm, with patients who convert having a lower mortality rate than those who do not. The drug prevented the development of new-onset AF and significantly reduced the VR in those with persistent AF.

Exercise Capacity and Mortality in Older Men A 20-Year Follow-Up Study

BACKGROUND Epidemiological findings, based largely on middle-aged populations, support an inverse and independent association between exercise capacity and mortality risk. The information available in older individuals is limited. METHODS AND RESULTS Between 1986 and 2008, we assessed the association between exercise capacity and all-cause mortality in 5314 male veterans aged 65 to 92 years (mean+/-SD, 71.4+/-5.0 years) who completed an exercise test at the Veterans Affairs Medical Centers in Washington, DC, and Palo Alto, Calif. We established fitness categories based on peak metabolic equivalents (METs) achieved. During a median 8.1 years of follow-up (range, 0.1 to 25.3), there were 2137 deaths. Baseline exercise capacity was 6.3+/-2.4 METs among survivors and 5.3+/-2.0 METs in those who died (P<0.001) and emerged as a strong predictor of mortality. For each 1-MET increase in exercise capacity, the adjusted hazard for death was 12% lower (hazard ratio=0.88; confidence interval, 0.86 to 0.90). Compared with the least fit individuals (< or =4 METs), the mortality risk was 38% lower for those who achieved 5.1 to 6.0 METs (hazard ratio=0.62; confidence interval, 0.54 to 0.71) and progressively declined to 61% (hazard ratio=0.39; confidence interval, 0.32 to 0.49) for those who achieved >9 METs, regardless of age. Unfit individuals who improved their fitness status with serial testing had a 35% lower mortality risk (hazard ratio=0.65; confidence interval, 0.46 to 0.93) compared with those who remained unfit. CONCLUSIONS Exercise capacity is an independent predictor of all-cause mortality in older men. The relationship is inverse and graded, with most survival benefits achieved in those with an exercise capacity >5 METs. Survival improved significantly when unfit individuals became fit.

Effect of Short-Term Infusion of Sodium Nitroprusside on Mortality Rate in Acute Myocardial Infarction Complicated by Left Ventricular Failure: Results of a Veterans Administration Cooperative Study

Eight hundred twelve men with presumed acute myocardial infarction and left ventricular filling pressure of at least 12 mm Hg participated in a randomized double-blind placebo-controlled trial to assess the efficacy of a 48-hour infusion of sodium nitroprusside. The mortality rates at 21 days (10.4 per cent in the placebo group and 11.5 per cent in the nitroprusside group) and at 13 weeks (19.0 per cent and 17.0 per cent, respectively) were not significantly affected by treatment. The efficacy of nitroprusside was related to the time of treatment: the drug had a deleterious effect in patients whose infusions were started within nine hours of the onset of pain (mortality at 13 weeks, 24.2 per cent vs. 12.7 per cent; P = 0.025) and a beneficial effect in those whose infusions were begun later (mortality at 13 weeks, 14.4 per cent vs. 22.3 per cent; P = 0.04). Nitroprusside should probably not be used routinely in patients with high left ventricular filling pressures after acute myocardial infarction. However, the results in the patients given late treatment suggest that those with persistent pump failure might receive sustained benefit from short-term nitroprusside therapy.

Noninvasive detection of coronary artery patency using continuous ST-segment monitoring

Continuous ST-segment Holter recordings were analyzed from 46 patients with acute myocardial infarction (AMI) receiving intracoronary streptokinase (SK) during the first 48 hours of hospitalization. Changes in ST deviation and the time periods of these changes were quantitated and correlated with angiographic evidence of reperfusion. Thirty-six patients had total occlusion of the infarct vessel and 10 had subtotal occlusion. Of the 36 vessels that were totally occluded, 19 were reperfused and 17 were not. In patients in whom reperfusion was successful, an ST steady state was achieved 55 +/- 32 minutes after SK administration. In patients in whom it was not successful, a steady state was achieved in 219 +/- 141 minutes (p less than 0.001). Achievement of steady state within 100 minutes after SK reperfusion indicated successful reperfusion with 89% sensitivity and 82% specificity. All patients with subtotal occlusion achieved an ST steady state before SK infusion. No patient with total occlusion achieved a steady state before SK. Achievement of ST steady state before SK infusion was 100% sensitive and 100% specific for subtotal occlusion at initial angiography. Continuous, quantitative ST-segment analysis is a sensitive and specific noninvasive technique for following coronary artery patency during AMI.

Effect of Amiodarone on Clinical Status and Left Ventricular Function in Patients With Congestive Heart Failure

BACKGROUND Although trials of amiodarone therapy in patients with congestive heart failure have produced discordant results with regard to effects on survival, most studies have reported a significant rise in left ventricular ejection fraction during long-term therapy. In the present study, we determined whether this increase in ejection fraction is associated with an improvement in the symptoms and/or physical findings of heart failure or a reduction in the number of hospitalizations for heart failure. METHODS AND RESULTS In the Department of Veterans Affairs cooperative study of amiodarone in congestive heart failure, 674 patients with New York Heart Association class II through IV symptoms and ejection fractions of < or = 40% were treated with amiodarone or placebo for a median of 45 months in a randomized, double-blind, placebo-controlled protocol. Clinical assessments and radionuclide ejection fraction were performed at baseline and after 6, 12, and 24 months. Compared with the placebo group, ejection fraction increased more in the amiodarone group at each time point (8.1 +/- 10.2% [mean +/- SD] versus 2.6 +/- 7.9% at 6 months, 8.0 +/- 10.9% versus 2.7 +/- 8.0% at 12 months, and 8.8 +/- 10.1% versus 1.9 +/- 9.4% after 24 months, all P < .001). However, this difference was not associated with greater clinical improvement, lesser diuretic requirements, or fewer hospitalizations for heart failure (11.1% for amiodarone and 13.6% for placebo group; overall relative risk in the amiodarone group, 0.81 [95% CI, 0.56 to 1.10], P = .18). Of note is the trend toward a reduction in the combined end point of hospitalizations and cardiac deaths (relative risk, 0.82 [CI, 0.65 to 1.03], P = .08), which was significant in patients with nonischemic etiology (relative risk, 0.56 [CI, 0.36 to 0.87], P = .01) and absent in the ischemic group (relative risk, 0.95). CONCLUSIONS Although amiodarone therapy resulted in a substantial increase in left ventricular ejection fraction in patients with congestive heart failure, this was not associated with clinical benefit in the population as a whole. The substantial reduction in the combined end point of cardiac death plus hospitalizations for heart failure in the nonischemic group suggests possible benefit in these patients.

Radiofrequency catheter ablation of ectopic atrial tachycardia using paced activation sequence mapping

OBJECTIVES Although ectopic atrial tachycardia is infrequent, it can be an important clinical challenge. We sought to define an alternative therapeutic approach to this refractory problem. BACKGROUND Radiofrequency energy catheter ablation has been used to treat a variety of ventricular and supraventricular arrhythmias but has not been proved efficacious in the management of ectopic atrial tachycardia. METHODS Ten patients (14 to 47 years of age) referred with refractory ectopic atrial tachycardia were studied. Mapping techniques included identification of earliest atrial activation, confirmation of concordance of P wave configuration during spontaneous tachycardia and pacing from the ablation catheter, and paced activation sequence mapping. The paced activation sequence mapping compared the activation sequence at multiple atrial sites during spontaneous tachycardia with that recorded during pacing from the ablation catheter. The catheter was steered to a point where pacing reproduced the spontaneous activation sequence. RESULTS Foci were right atrial in eight patients and left atrial in two. In 8 of 10 patients, 514 +/- 97 (SE) J and 5.7 +/- 2.3 (SD) J radiofrequency energy applications ablated the ectopic focus. Seven of these eight patients presented with one focus and one had two discrete and stable foci. Ablation was unsuccessful in two patients with multiple foci. No complications occurred. An arrhythmia focus recurred in two patients and one patient underwent successful repeat ablation. The other patient was managed medically. All seven patients with successful ablation are symptom free after 6.5 +/- 3.8 months. CONCLUSIONS Our preliminary experience suggests that with the use of both paced activation sequence mapping and standard techniques, radiofrequency ablation of ectopic atrial tachycardia may be a safe and effective form of therapy.

Serial electrocardiographic changes in idiopathic dilated cardiomyopathy confirmed at necropsy

Serial electrocardiographic changes in necropsy-proven idiopathic dilated cardiomyopathy are evaluated and a method of predicting heart weight using QRS amplitudes is described. In 34 patients with multiple electrocardiograms (mean 3/patient) progressive prolongation of PR interval (0.18 +/- 0.03 to 0.21 +/- 0.03, p less than 0.001) and QRS duration (0.10 +/- 0.02 to 0.13 +/- 0.03, p less than 0.0001) was noted. Progressive conduction abnormalities were common (82%). QTc interval and QRS- and T-wave axes did not change. In 50 patients with electrocardiograms within 60 days of death, total 12-lead QRS and V1 through V6 QRS amplitude correlated better with heart weight (r = 0.51, p less than 0.0001 and r = 0.55, p less than 0.0001) than the Estes-Romhilt score did. The mean total 12-lead QRS amplitude was 138 mm with a mean of 106 for V1 through V6. In 31 patients cardiac mass index was calculated and showed significant correlation with 12-lead and V1 through V6 QRS amplitudes (r = 0.68, p less than 0.0001 and r = 0.75, p less than 0.0001, respectively). The QRS amplitudes remained constant during the illness. By using total 12-lead QRS or frontal plane QRS amplitude, heart weight can be predicted as early as 2 years before death. Use of body surface area and QRS amplitude criteria increases the accuracy of heart weight prediction. Thus, progressive electrocardiographic changes are common in patients with idiopathic dilated cardiomyopathy and QRS amplitude criteria are more accurate in the prediction of left ventricular hypertrophy than standard criteria.