Norma Medina

Comparison of Captopril and Enalapril in Patients with Severe Chronic Heart Failure

To evaluate the concept that long duration of action is an advantageous property of angiotensin-converting enzyme inhibitors in the treatment of severe heart failure, we randomly assigned 42 patients to therapy with either a short-acting inhibitor (captopril, 150 mg daily) or a long-acting inhibitor (enalapril, 40 mg daily) for one to three months while concomitant therapy with digoxin and diuretics was kept constant. The treatment groups had similar hemodynamic and clinical characteristics at base-line evaluation and similar initial responses to converting-enzyme inhibition. During long-term therapy, captopril and enalapril produced similar decreases in systemic blood pressure, but the hypotensive effects of enalapril were more prolonged and persistent than those of captopril. Consequently, although the patients in both groups improved hemodynamically and clinically during the study, serious symptomatic hypotension (syncope and near syncope) was seen primarily among those treated with enalapril. Sustained hypotension also probably accounted for the decline in creatinine clearance (P less than 0.05) and the notable retention of potassium (P less than 0.05) observed in the patients treated with enalapril but not in those treated with captopril. We conclude that when large, fixed doses of converting-enzyme inhibitors are used in the treatment of patients with severe chronic heart failure, long-acting agents may produce prolonged hypotensive effects that may compromise cerebral and renal function, and thus they may have disadvantages in such cases, as compared with short-acting agents.

Functional renal insufficiency during long-term therapy with captopril and enalapril in severe chronic heart failure.

Renal function was evaluated in 104 patients with severe chronic heart failure whom we treated with captopril or enalapril. Seventy patients showed no change or an improvement in renal function (group A), and 34 patients developed functional renal insufficiency (group B). Before converting-enzyme inhibition, group B patients received higher doses of furosemide (p less than 0.02) and had lower central venous pressures (p less than 0.05) than group A patients. After 1 to 3 months of converting-enzyme inhibition, an excessive reduction in left ventricular filling pressure (to less than 15 mm Hg) or mean arterial pressure (to less than 60 mm Hg) was noted in 28 of 34 (82%) patients in group B but in only 22 of 70 patients in group A (31%) (p less than 0.001). At the end of the study, drug-induced azotemia resolved after a reduction in the dosage of diuretics, despite unaltered treatment with captopril and enalapril. Hence, the deterioration of renal function after converting-enzyme inhibition in heart failure is not a toxic or immunologic reaction to therapy but results from specific hemodynamic events that can be ameliorated by sodium repletion.

Correction of Dilutional Hyponatremia in Severe Chronic Heart Failure by Converting-Enzyme Inhibition

To determine the effects of vasodilator and inotropic therapy on hyponatremia in patients with severe heart failure, we measured serum sodium concentration before and after treatment with captopril (70 patients), hydralazine (42 patients), prazosin (22 patients), and amrinone (19 patients), while diuretic dosages were kept constant. Serum sodium concentration increased only in hyponatremic patients treated with captopril (131.2 +/- 0.5 to 135.9 +/- 0. 5 SE ; p less than 0.001), but not during therapy with the other agents and not in patients with normal serum sodium concentration before treatment. Serum sodium began to rise 48 hours after the initiation of captopril therapy and reached its peak after 14 to 16 days. Correction of hyponatremia was related to functional interference with the renin-angiotensin system, but not to changes in renal function, serum potassium concentration, body weight, or the magnitude of hemodynamic or clinical improvement. These findings support experimental evidence that the renin-angiotensin system is important in the pathogenesis of hyponatremia in patients with severe heart failure treated with diuretics.

Rebound Hemodynamic Events after the Abrupt Withdrawal of Nitroprusside in Patients with Severe Chronic Heart Failure

We studied the hemodynamic events that followed abrupt withdrawal of nitroprusside in 20 patients with severe chronic heart failure. With nitroprusside, cardiac index increased from 1.96 to 2.87 liters per minute per square meter of body-surface area, but it decreased to 1.66 (P less than 0.001) after withdrawal of nitroprusside. Left ventricular filling pressure and systemic vascular resistance decreased from 23.9 to 15.3 mm Hg and from 1642 to 921 dyn.sec.cm-5, respectively, with nitroprusside, but increased to 30.4 mm Hg and 2109 dyn.sec.cm-5 (both P less than 0.001) upon its discontinuation. These rebound changes were maximal 10 to 30 minutes after nitroprusside withdrawal and returned to control levels one to three hours later. Although in 17 of 20 patients, these rebound changes caused no or minimal exacerbation of symptoms, pulmonary edema, which resolved in three patients. Activation of reflex vasoconstrictive forces during vasodilator therapy may explain these effects of withdrawal.

Identification of hyponatremia as a risk factor for the development of functional renal insufficiency during converting enzyme inhibition in severe chronic heart failure.

To identify patients with severe chronic heart failure who are at greatest risk of developing functional renal insufficiency during converting enzyme inhibition, creatinine clearance was measured in 59 patients before and after long-term therapy with captopril (39 patients) or enalapril (20 patients), while digitalis and diuretic therapy was kept constant. Creatinine clearance increased or remained constant in 33 of the 59 patients (Group I), but declined in the remaining 26 patients (Group II). The two groups were similar with respect to the cause of heart failure, pretreatment renal function and all pretreatment hemodynamic variables. Patients in Group II, however, had lower values for serum sodium concentration (134.8 +/- 1.0 versus 137.0 +/- 0.6 mmol/liter) and higher values for plasma renin activity (10.6 +/- 3.4 versus 3.0 +/- 0.5 ng/ml per hour), received larger doses of furosemide (108 +/- 11 versus 84 +/- 6 mg/day), were more frequently diabetic (42 versus 15%) and were more frequently treated with enalapril (50 versus 21%) than were patients in Group I (all p less than 0.05). By stepwise logistic analysis, only hyponatremia (or an elevated plasma renin activity) and enalapril therapy independently predicted the decline in creatinine clearance during converting enzyme inhibition. These observations could not be explained by changes in systemic blood pressure. In patients with a normal serum sodium concentration (greater than or equal to 137 mmol/liter), creatinine clearance increased with captopril (+21%, p less than 0.05), but not with enalapril (-6%, p = NS).(ABSTRACT TRUNCATED AT 250 WORDS)

Adverse hemodynamic and clinical effects of calcium channel blockade in pulmonary hypertension secondary to obliterative pulmonary vascular disease

The hemodynamic and clinical responses to calcium channel blockade with verapamil and nifedipine were compared with those of hydralazine in 12 patients with pulmonary hypertension secondary to obliterative pulmonary vascular disease. All three drugs produced a marked and similar decrease in pulmonary vascular resistance; however, this was accompanied by a significant increase in cardiac index with hydralazine (+0.71 liter/min per m2, p less than 0.01), no change in cardiac index with nifedipine and a significant decrease in cardiac index with verapamil (-0.25 liter/min per m2, p less than 0.05). Mean pulmonary artery pressure decreased markedly with both calcium channel blocking drugs (-16.0 mm Hg with verapamil and -14.5 mm Hg with nifedipine, both p less than 0.01), but this was associated with a concomitant increase in mean right atrial pressure (+6.2 mm Hg with verapamil and +4.4 mm Hg with nifedipine, both p less than 0.01); neither variable changed after hydralazine. Hence, right ventricular performance (as reflected by right ventricular stroke work index) deteriorated during treatment with both calcium channel blocking drugs, despite the decrease in resistance to right ventricular ejection; in contrast, right ventricular stroke work index increased after hydralazine. The unfavorable hemodynamic effects of calcium channel blockade were accompanied by severe adverse clinical events, including profound hypotension and cardiogenic shock during acute drug administration and the exacerbation of right heart failure during long-term treatment. These deleterious responses to verapamil and nifedipine are likely the result of a direct depressant effect exerted by these drugs on right ventricular function independent of their pulmonary vasodilatory actions.

Hemodynamic Characterization of Tolerance to Long-Term Hydralazine Therapy in Severe Chronic Heart Failure

We performed hemodynamic studies in 11 patients with severe chronic heart failure whose symptoms had returned to their pretreatment status after 37 +/- 15 weeks (mean +/- S.E.M.) of therapy with the vasodilator hydralazine. The cardiac index increased from 1.85 to 3.47 liters per minute per square meter of body-surface area, and systemic vascular resistance decreased from 1748 to 754 dyn . sec. cm-5 (both p less than 0.01) during initial hydralazine administration but returned to pretreatment values on repeat evaluation; withdrawal of the drug produced no hemodynamic deterioration. Responsiveness to hydralazine could not be restored by doubling the oral dose or by intravenous administration; tolerance was associated with fluid retention in five patients but was not reversed by intensive diuresis. In contrast, the responses to nitroprusside evaluated before and after the development of hydralazine tolerance were unaltered; other oral vasodilators were still effective. We conclude that drug-specific tolerance may account for the lack of clinical improvement in some patients with severe heart failure who receive long-term treatment with hydralazine.

Prognostic importance of the immediate hemodynamic response to nifedipine in patients with severe left ventricular dysfunction

To determine the clinical significance of the occurrence of hemodynamic deterioration after the administration of calcium channel blocking drugs, nifedipine (20 mg orally) was administered to 29 patients with severe left ventricular dysfunction. Thirteen patients showed hemodynamic improvement with the drug (Group 1), as shown by a notable increase in cardiac index associated with a modest decrease in mean arterial pressure. The other 16 patients exhibited hemodynamic deterioration after nifedipine (Group 2), as reflected by a decline in right and left ventricular stroke work indexes accompanied by a marked hypotensive response. These differences were not related to differences in the peripheral vascular response to nifedipine, because both groups showed similar decreases in systemic and pulmonary vascular resistances. Groups 1 (hemodynamic improvement) and 2 (hemodynamic deterioration) were similar with respect to all demographic variables and pretreatment left ventricular performance (cardiac index, left ventricular filling pressure and systemic vascular resistance). Yet, the 1 year actuarial survival in patients in Group 1 was substantially better than that in patients in Group 2 (67 versus 23%, p = 0.009). Group 2, however, had higher values for plasma renin activity (17.7 +/- 6.0 versus 4.3 +/- 1.4 mg/ml per h, p less than 0.05), lower values for serum sodium concentration (134.6 +/- 1.2 versus 139.2 +/- 0.6 mEq/liter, p less than 0.05) and higher values for mean right atrial pressure (15.8 +/- 2.0 versus 7.9 +/- 1.4 mm Hg, p less than 0.01) than did patients in Group 1.(ABSTRACT TRUNCATED AT 250 WORDS)

Comparative hemodynamic effects of procainamide, tocainide, and encainide in severe chronic heart failure.

Many of the newer antiarrhythmic agents are said to cause minimal myocardial depression, but their hemodynamic effects have not been invasively evaluated and compared in patients with severe chronic heart failure. In a randomized, crossover study, the hemodynamic responses to single oral doses of procainamide (750 mg), tocainide (600 mg), and encainide (50 mg) given to 21 patients with severe chronic heart failure were compared. Cardiac performance decreased with all three drugs, but the magnitude of deterioration differed among the three agents. Stroke volume index decreased with procainamide (-5 +/- 1 ml/m2, p less than 0.001), tocainide (-7 +/- 1 ml/m2, p less than 0.001), and encainide (-8 +/- 1 ml/m2, p less than 0.001), but the decline was significantly greater with encainide than with procainamide (p less than 0.05). Similarly, left ventricular filling pressure increased with tocainide and encainide (+4 +/- 1 and +5 +/- 2 mm Hg, respectively; both p less than 0.05), but not with procainamide; the increase was significantly greater with tocainide and encainide than with procainamide (p less than 0.001). These deleterious hemodynamic effects were accompanied by worsening symptoms of heart failure in six patients with encainide and seven patients with tocainide but in only two patients with procainamide. Serum levels for all drugs were in the therapeutic range. In conclusion, although the three type I antiarrhythmic agents tested may all adversely affect left ventricular function in patients with heart failure, encainide and tocainide are more likely than procainamide to cause hemodynamic and clinical deterioration.

Hemodynamic factors limiting the response to transdermal nitroglycerin in severe chronic congestive heart failure

Abstract To clarify the continuing controversy concerning the use of transdermal nitroglycerin (MN), the short-term hemodynamic responses to sublingual, oral and transcutaneous nitrates were evaluated and compared in 22 patients with severe chronic congestive heart failure. Sixteen patients showed favorable hemodynamic effects with TDN, but the doses needed to achieve this response varied greatly: 10 mg/24 hours in 6 patients, 20 mg/24 hours in 5 patients, 40 mg/24 hours in 3 patients and 60 mg/24 hours in 2 patients. Of the 6 remaining patients, 3 did not respond to high-dose TDN even though they showed marked effects after sublingual and oral nitrate administration; 3 others did not respond to any nitrate formulation by any route. TDN produced immediate increases in cardiac index and decreases in right and left ventricular filling pressure, mean arterial pressure and systemic vascular resistance (p In conclusion, the use of TDN in patients with severe chronic congestive heart failure is limited by the large doses of the drug that are needed in some patients, by the rapid attenuation of its beneficial effects during prolonged therapy, by the potential for cross tolerance to other nitrates, and by the occurrence of rebound phenomena after drug withdrawal.