Felix E. Tristani

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.

Exercise stress testing. Correlations among history of angina, ST-segment response and prevalence of coronary-artery disease in the Coronary Artery Surgery Study (CASS).

Abstract To determine to what extent the diagnostic accuracy of stress testing is influenced by the prevalence of coronary-artery disease, we correlated the description of chest pain, the result of stress testing and the results of coronary arteriography in 1465 men and 580 women from a multicentered clinical trial. The pre-test risk (prevalence of coronary-artery disease) varied from 7 to 87 per cent, depending on sex and classification of chest pain. A positive stress test increased the pre-test risk by only 6 to 20 per cent, whereas a negative test decreased the risk by only 2 to 28 per cent. Although the percentage of false-positive results differed between men and women (12±1 per cent versus 53±3 per cent P < 0.001), this difference was not seen in a subgroup matched for prevalence of coronary-artery disease. We conclude that the ability of stress testing to predict coronary-artery disease is limited in a heterogeneous population in which the prevalence of disease can be estimated through classificat...

Prognostic importance of a clinical profile and exercise test in medically treated patients with coronary artery disease

To identify predictors of mortality in medically treated patients with symptomatic coronary artery disease, 30 variables were analyzed in 4,083 patients. Regression analysis demonstrated that seven variables were independent predictors of survival. A high risk subgroup (annual mortality rate above 5%) was identified, consisting of patients with either a congestive heart failure score of 3 to 4 or 1 mm or greater ST segment depression and final exercise stage of 1 or less. When all 30 variables were analyzed conjointly, the left ventricular contraction pattern (p less than 0.0001) and the number of diseased coronary vessels (p less than 0.003) proved to be the most important predictors of survival. In a subgroup of 572 patients with three vessel coronary disease and preserved left ventricular function, the probability of survival at 4 years ranged from 53% for patients only able to achieve stage 1/2 of exercise to 100% for patients able to exercise into stage 5 (p less than 0.004). Thus, in patients with defined coronary pathoanatomy, clinical and exercise variables primarily relating to the functional state of the left ventricle are helpful in assessing prognosis.

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.

Significance of silent myocardial ischemia during exercise testing in patients with coronary artery disease.

To evaluate the significance of ischemic ST-segment depression without associated chest pain during exercise testing, data were analyzed from 2,982 patients from the Coronary Artery Surgery Study (CASS) registry who underwent coronary arteriography and exercise testing and were followed up for 7 years. Patients with proved coronary artery disease (CAD) (at least 70% diameter narrowing) were grouped according to whether they had at least 1 mm of ST-segment depression or anginal chest pain during exercise testing. Four hundred twenty-four had ischemic ST depression without angina (group 1); 232 had angina but no ischemic ST depression (group 2); 456 had both ischemic ST depression and angina (group 3); and 471 had neither ischemic ST depression nor angina (group 4). Sixty-three percent of patients in group 1 and 55% in group 2 had multivessel CAD (difference not significant). The 7-year survival rates were similar for patients in groups 1 (76%), 2 (77%), and 3 (78%), but were significantly better for patients in group 4 (88%, p less than 0.001). Among group 1 patients, survival was related to severity of CAD (p less than 0.001). The 7-year survival rate in group 1 was significantly worse than that in a separate group of 282 patients with ischemic ST depression without angina during exercise testing who had no CAD (95% survival, p less than 0.001). Thus, in patients with silent myocardial ischemia during exercise testing, the extent of CAD and the 7-year survival rate are similar to those of patients with angina during exercise testing. Prognosis is determined primarily by the severity of CAD. In patients without CAD, the survival rate is excellent.

Determination of stroke volume and cardiac output during exercise: comparison of two-dimensional and Doppler echocardiography, Fick oximetry, and thermodilution.

Simultaneous estimates of cardiac output were made during graded upright maximal exercise in 10 male subjects by means of Doppler velocity spectrum of ascending aortic flow, apical two-dimensional echocardiograms, thermodilution, and Fick oximetry. In 15 subjects, aortic annular and root diameters were measured during similar exercise from parasternal two-dimensional echocardiograms. The linear correlation between Doppler, two-dimensional echocardiography, and the invasive estimates ranged from r = .78 to r = .92. Both echocardiographic techniques were able to predict changes in invasive flow estimates with reasonable accuracy. Two-dimensional echocardiographic flow estimates underestimated invasive values by about 60%. The accuracy of Doppler flow estimates varied with the method of estimating aortic cross-sectional area. Greatest accuracy was obtained with areas calculated from diameters measured at the aortic value anulus with the leading edge-to-leading edge method of measurement. Correlation coefficients comparing Doppler and thermodilution flow estimates were generally higher (r = .75 to .96, mean .86) for individuals than for the group, but accuracy of the Doppler estimates in single subjects was quite variable. Aortic diameters did not increase from rest to moderate levels of upright exercise. A 3% to 5% increase in resting aortic diameter was noted in the upright posture as compared with the supine. Doppler flow estimates were obtained in all subjects to maximal exertion but in only a minority of subjects with two-dimensional echocardiography or thermodilution. Thus two-dimensional and Doppler echocardiography offer a noninvasive means of estimating cardiac output during vigorous exercise. The Doppler technique is technically more suitable to the study of exercise than two-dimensional echocardiography.(ABSTRACT TRUNCATED AT 250 WORDS)

Systemic and Renal Hemodynamics in Oliguric Hepatic Failure: Effect of Volume Expansion*

Systemic and renal hemodynamics were studied by indicator dilution techniques before and after infusion of 500 ml of dextran 40 in 21 patients with renal failure developing in the course of decompensated cirrhosis. Cardiac index was directly correlated with total blood volumes. Renal blood flow was low and renal vascular resistance elevated in 13 of 15 patients. Renal vascular resistance was directly related to total systemic nonrenal vascular resistance. Two patients with the highest cardiac outputs in the group were oliguric with high renal blood flow. Plasma volume expansion increased cardiac output in 19 of 21 patients and increased renal blood flow in 12 of 14. The patients were divided into two groups on the basis of control cardiac index. Those with lower cardiac index had lower blood volumes and responded to dextran with a 73% increase in cardiac output, a 148% increase in renal blood flow, and a rise in renal fraction. Those with high control cardiac index had significantly higher blood volumes and responded to dextran with only a small average rise in cardiac output and renal blood flow. Systolic arterial pressure was less than 100 mm Hg in 12 patients. When compared to the normotensive subjects, this hypotension was characterized by a lower vascular resistance, a tendency for a lesser rise in renal blood flow after volume expansion, and a more rapid demise. The prompt circulatory improvement after volume expansion in many of these patients indicates that functional plasma volume depletion may be an important factor in the renal vasoconstriction of oliguric hepatic failure. In an attempt to sustain volume expansion, reinfusion of ascitic fluid was accomplished in four patients. Normal renal blood flow was maintained during reinfusion and a diuresis always occurred, but the response usually was not maintained after the infusion was terminated.

The role of exercise testing in identifying patients with improved survival after coronary artery bypass surgery

To determine whether exercise testing can identify patients whose survival might be prolonged by coronary artery bypass surgery, the results of bypass surgery were compared with those of medical therapy alone in 5,303 nonrandomized patients from the Coronary Artery Surgery Study registry who underwent exercise testing. Patients in the two treatment groups differed substantially with regard to important baseline variables. Analysis of 32 variables by Coxs regression model for survival revealed an independent beneficial effect of bypass surgery on survival (p less than 0.00001). Patients were then stratified into subsets according to the results of exercise testing. Surgical benefit was greatest in the 789 patients who exhibited at least 1 mm of ST segment depression and who could exercise only into stage 1 or less. Among the 398 patients with three vessel coronary disease showing these characteristics, 7 year survival was 58% for the medical group and 81% for the surgical group (p less than 0.001). There was no difference in survival between the surgical and medical groups among the 1,545 patients without ischemic ST segment depression who were able to exercise into stage 3 or greater. Thus, in patients who demonstrate ischemia on exercise testing and whose exercise capacity is limited, coronary bypass surgery appears to improve survival in comparison with medical therapy alone.

Cardiac and peripheral vascular effects of digitalis in clinical cardiogenic shock

Abstract The hemodynamic effects of cardiac glycosides were studied in 13 patients with cardiogenic shock. Intravenous administration of ouabain, deslanoside, or digoxin produced a prompt pressor effect which was characterized by increases in systemic vascular resistance and tension time index and no change or increase in right atrial pressure (RAP) and left ventricular enddiastolic pressure (LVEDP). Acute pulmonary edema developed during this period in one patient. During the later phase, 15 to 60 minutes after infusion of digitalis, there were increases in the maximum rate of rise of left ventricular pressure (LV dp dt ), mean systolic ejection rate, and left ventricular stroke work usually with a fall in RAP or LVEDP. Despite the evidence of improved myocardial function, cardiac output (CO) was not significantly increased and was always lower than that attained during infusion of isoproterenol. It is concluded that digitalis is not very effective by itself in restoring blood flow in cardiogenic shock and that the early peripheral vasoconstrictor effect following intravenous administration may be deleterious in some patients.