Oral amrinone for the treatment of chronic congestive heart failure: results of a multicenter randomized double-blind and placebo-controlled withdrawal study.

A placebo-controlled study was employed to evaluate the effects of oral amrinone in patients with congestive heart failure. After a baseline period of at least 4 weeks of standard treatment for refractory congestive heart failure, oral amrinone was added to the treatment regimen of 173 patients. Patients were predominantly male (89%), aged 24 to 76 years (mean 54), with ischemic (52%) or idiopathic (37%) dilated cardiomyopathy, in New York Heart Association functional class II (40%), III (59%) and IV (1%) and having a mean (+/- standard deviation) left ventricular ejection fraction of 25 +/- 15%. Phase 1: After the addition of amrinone (113 +/- 33 mg three times daily), 52 patients (30%) showed a maximal increase in treadmill exercise time exceeding 2 minutes (Naughton protocol), 72 (42%) had a lesser increase, 24 (14%) developed limiting adverse reactions, 20 (12%) died and 5 dropped out of the study. Fifty-two "responders" (30%) who were free of limiting side effects and had a greater than 2 minute increase in exercise time were randomized in double-blind fashion to continued amrinone or switched to placebo (each plus standard treatment) for an additional 12 weeks. Phase 2: Comparison of 31 of these 52 responders who continued to receive amrinone with the remaining 21 randomized to placebo revealed no significant differences in vital signs, indexes of left ventricular size and function, systolic time intervals or maximal exercise time. Continued follow-up study of patients receiving either amrinone or placebo revealed decreases in exercise times of 7 and 10%, respectively (both p less than 0.05 compared with before randomization). Episodes of worsened congestive heart failure severe enough to mandate termination of double-blind treatment were as frequent in patients taking placebo (4[18%] of 21) as in those taking amrinone (4[13%] of 31; p = NS). The average symptom score and functional class of each treatment group remained comparable. Adverse effects such as gastrointestinal and central nervous system complaints were more common with amrinone treatment as were elevations of serum liver enzymes and reduced platelet counts. This large multicenter, randomized double-blind withdrawal study revealed no change in estimates of cardiac performance after the discontinuation of amrinone. These findings suggest that amrinone, in the dosages tested, does not importantly improve cardiac function beyond that provided by standard treatment with digoxin, diuretic drugs and vasodilators.

Amrinone-induced thrombocytopenia.

The frequency and characteristics of thrombocytopenia resulting from administration of amrinone, a new inotropic and vasodilator agent, was evaluated in 43 patients. Thrombocytopenia attributable to amrinone developed in eight patients (18.6%). The thrombocytopenia was due to accelerated peripheral loss of platelets. There appeared to be a dose relationship with regard to the rapidity of onset and degree of thrombocytopenia. Although platelet-associated IgG levels were elevated when measured in patients with thrombocytopenia, the clinical features were suggestive of a direct, perhaps nonimmunologic effect of amrinone on platelets. Thrombocytopenia was mild in most cases and bleeding attributable to thrombocytopenia did not occur. Several patients continued amrinone therapy over long periods despite low platelet counts, showing that mild to moderate thrombocytopenia is not necessarily an indication that therapy should be discontinued, but that platelet counts should be observed closely.

Pulmonary artery pseudoaneurysm. A potential complication of pulmonary artery catheterization.

A 70-year-old woman with pulmonary hypertension due to severe chronic obstructive pulmonary disease and long-standing mitral stenosis developed hemoptysis and a right upper lobe infiltrate during manipulation of a balloon-tipped flow-directed pulmonary artery catheter. Hemoptysis resolved spontaneously over several minutes, and the right upper lobe infiltrate cleared over several weeks, during which time a new right upper lobe nodule became apparent. Angiography disclosed the presence of a late-filling well-circumscribed saccular pseudoaneurysm. This was obliterated with an acute infiltrate with or without hemoptysis in the area subtended by a flow-director pulmonary artery catheter, and particularly when it is associated with manipulation of that catheter, the differential diagnosis should include pulmonary artery perforation as well as infarction. If the patient survives the episode, the possibility that a pseudoaneurysm has formed must be actively entertained and aggressively evaluated, since pseudoaneurysm is a potentially fatal lesion that is treatable.

Heart disease and hypertension in severe obesity: the benefits of weight reduction.

Severe obesity is associated with abnormalities of cardiac structure and function. These include an increased cardiac workload and ventricular hypertrophy. Hypertension in combination with severe obesity seriously burdens the heart because the increased preload and afterload compound cardiac work. Weight reduction induced by gastric operations for severe obesity is associated with resolution of hypertension, reduction in ventricular wall thickness and cardiac chamber size, as well as improved systolic function. Additional data are needed to predict when in the course of development of obese cardiomyopathy the changes in contractile function become irreversible. Additionally, the impact of coronary artery disease on the progression of obese cardiomyopathy and the effects of surgical weight reduction on cardiac structure and function need to be further clarified. Studies of the association between obesity, its treatment, and modification of cardiovascular risk are a major focus of preventive cardiology today.

Comparative vasoactive therapy for heart failure.

Dopamine and dobutamine increase myocardial contractility by beta-adrenergic stimulation. Both agents provide significant support for decompensating congestive heart failure (CHF) patients. At the same time, both agents can have significant adverse effects. In 1981, it was reported that amrinone, a bipyridine derivative, produced hemodynamic changes similar to those of dobutamine. To confirm these results, the hemodynamic and clinical effects of amrinone were compared with those of dopamine and dobutamine in 15 consecutive patients with CHF. Although each drug improved maximal cardiac index to a similar extent, dopamine did not decrease pulmonary artery wedge pressure and caused a greater increase in heart rate. Dobutamine and amrinone conferred similar hemodynamic benefits: cardiac index improved from 2.4 +/- 0.2 to 3.4 +/- 0.2 liters/min/m2 with dobutamine and from 2.1 +/- 0.2 to 3.2 +/- 0.2 liters/min/m2 with amrinone. Pulmonary artery wedge pressure decreased similarly: from 19 +/- 2 to 13 +/- 1 mm Hg with dobutamine and from 18 +/- 2 to 12 +/- 1 mm Hg with amrinone. Dobutamine and amrinone produced similar modest decreases in mean arterial pressure and increments in heart rate. Dopamine was poorly tolerated; 5 patients developed such severe adverse reactions that this drug was discontinued prematurely. Dobutamine and amrinone were much better tolerated. Although amrinone caused asymptomatic tachycardia (heart rate increase greater than 20% over baseline) in 4 patients, no patient developed an adverse reaction warranting its premature termination.

Pharmacokinetics and pharmacodynamics of milrinone in chronic congestive heart failure.

The acute hemodynamic effects and pharmacokinetics of bolus intravenous milrinone administration were assessed in 13 patients with severe congestive heart failure. Serial hemodynamics were measured and blood samples were obtained to determine plasma milrinone concentration and calculation of pharmacokinetic variables after administration of milrinone at 12.5, 25, 50 and 75 micrograms/kg, allowing at least 6 hours to elapse between consecutive milrinone doses. At each dose milrinone effected prompt but very short-lived increases in cardiac output and left ventricular stroke work and decreases in pulmonary artery pressure, right atrial pressure and systemic and pulmonary vascular resistance in a non-dose-dependent fashion. Pulmonary artery wedge pressure decreased in a dose-related manner. Heart rate increased significantly after the 75-micrograms/kg dose and mean arterial pressure decreased significantly only after the 50- and 75-micrograms/kg milrinone dose. The time-dependent decline in plasma milrinone concentration was biexponential and log linear, conforming to an open 2-compartment model of drug distribution and elimination. Mean plasma milrinone clearance (+/- standard error) was 0.15 +/- 0.03 liters/min/kg, volume of distribution was 0.35 +/- 0.02 liters/kg and mean elimination half-life was 1.7 hours.

Assessment of hemodynamic tolerance from a 24-hour intravenous infusion of fenoldopam mesylate in congestive heart failure.

To determine the maintenance of pharmacodynamic effects of fenoldopam mesylate, a dopamine-1 agonist, the invasive hemodynamic profiles of 33 patients with New York Heart Association functional class III to IV congestive heart failure were examined. Fenoldopam mesylate was initiated at 0.1 micrograms/kg/min and titrated to a cardiac index greater than or equal to 25% above baseline. Upon achievement of optimal hemodynamics, maintenance infusion was begun (mean dose 0.6 micrograms/kg/min). Fenoldopam mesylate (baseline vs maximal effect) decreased systemic vascular resistance by 37% (p less than 0.001), left ventricular filling pressure by 16% (p less than 0.05) and mean arterial pressure by 11% (p less than 0.05), with an associated augmentation in cardiac index and stroke volume index by 27% (p less than 0.001). Attenuation of hemodynamic effect (maximal effect vs time) was noted in cardiac index (14% p less than 0.001), systemic vascular resistance (13% p less than 0.05) and stroke volume index (13% p less than 0.05). None of the parameters exhibited complete attenuation to baseline values. Fenoldopam mesylate improves cardiac output and lowers systemic vascular resistance with relative attenuation of pharmacodynamic effect during a 24-hour intravenous infusion.

Oral amrinone in refractory congestive heart failure.

The acute effects of an oral preparation of amrinone, a recently synthesized cardiotonic agent, were assessed noninvasively in nine patients who had advanced heart failure that persisted despite treatment with digitalis, diuretic drugs and afterload-reducing agents. All patients demonstrated an improvement in left ventricular ejection fraction determined by radionuclide ventriculography (20.3 +/- 2.8 to 30.8 +/- 4.8 percent [mean +/- standard error of the mean], p less than 0.005) after a single dose of amrinone. Initial effects were seen within 1 hour, with the peak effect occurring at 1 to 3 hours; persistent effects were demonstrable at 4 to 6 hours. No change in blood pressure, heart rate or rhythm was observed, and there was no clinical evidence of myocardial ischemia. Continued benefit was demonstrated by radionuclide ventriculography in two patients treated for 1 and 6 weeks, respectively, although two other patients experienced major side effects with the chronic administration of amrinone. Although orally administered amrinone shows promise as a potentially useful agent in the treatment of advanced heart failure, the safety of this drug remains to be established.

Hemodynamic effects of intravenous bepridil in patients with normal left ventricular function.

Calcium-channel blockers are known to have depressant effects on atrioventricular (AV) nodal conduction and myocardial contractility. Because of these known depressant effects, bepridil hydrochloride, a new, long-acting, antianginal and antiarrhythmic calcium-channel blocker, was administered intravenously to patients without heart failure to determine acute hemodynamic effects. The patients studied had normal ventricular function, were without electrocardiographic conduction disturbances and were taking no drug except sublingual nitroglycerin for at least 24 hours before bepridil infusion. The study protocol included right- and left-sided cardiac catheterization with infusion of bepridil at 2 mg/kg for 15 minutes followed by 1 mg/kg for 15 minutes in 10 patients, and infusion of bepridil at 3 mg/kg for 15 minutes followed by 1 mg/kg for 15 minutes in 8 patients. Pressures, Fick cardiac output, resistances, left ventricular (LV) dP/dt, LV stroke work index and rate-pressure product of the left ventricle were monitored. There were no significant changes during bepridil infusion at either dose for cardiac output, systemic vascular and pulmonary vascular resistances, LV stroke work index, heart rate, arterial blood pressure and rate-pressure product. There was mild depression of LV dP/dt during bepridil infusion. Further, LV end-diastolic pressure, pulmonary capillary wedge pressure and pulmonary arterial pressures were significantly increased during bepridil infusion. There were no apparent changes in AV nodal or intraventricular conduction during bepridil infusion. We conclude that bepridil appears to be a safe drug for intravenous administration despite mild depression of myocardial function in patients with normal baseline hemodynamic function who are not receiving concomitant beta-blocker therapy.

Comparison of intravenous milrinone and dobutamine for congestive heart failure secondary to either ischemic or dilated cardiomyopathy.

Milrinone and dobutamine are positive inotropic agents with beneficial hemodynamic effects in patients with congestive heart failure. This study was undertaken to compare the effects of intravenous milrinone and dobutamine in patients with stable New York Heart Association class III or IV congestive heart failure and to test the hypothesis that intravenous milrinone is at least as beneficial as dobutamine in this setting. Seventy-nine patients were randomized to either dobutamine therapy at incremental doses of 2.5, 5, 7.5, 10, 12.5 and 15 micrograms/kg/min, or milrinone as a bolus of 50 or 75 micrograms/kg followed by an infusion of 0.5 to 1.0 micrograms/kg/min. Both agents significantly increased heart rate, cardiac index and stroke volume index and decreased pulmonary artery wedge pressure and systemic vascular resistance compared with baseline levels (p less than 0.01). During sustained infusion for 48 hours, no difference in hemodynamic effects was observed between the 2 drugs. Ventricular tachycardia occurred in 5 patients (3 taking milrinone, 2 taking dobutamine); 1 patient taking milrinone had ventricular fibrillation. Milrinone and dobutamine elicited similar beneficial hemodynamic results with relatively few adverse effects.

Aortic and mitral insufficiency complicating fulminant systemic lupus erythematosus.

The cardiac complications of systemic lupus erythematosus (SLE) include a multitude of valvular, myocardial, and pericardial abnormalities resulting from acute and chronic inflammation involving the endocardium, myocardium, and/or pericardium. A case of acute, severe, aortic, and mitral insufficiency occurring as discrete complications of consecutive flares of SLE in the same patient is described with particular emphasis on the clinical and gross pathologic findings. The cardiac complications of SLE, both from a pathologic and clinical standpoint, are reviewed in the context of the uniqueness of this case.

The clinical profile of unresolved pulmonary embolism.

Nearly all patients with pulmonary embolism (PE) have complete clinical and hemodynamic and at least near complete roentgenographic and angiographic resolution within four to six weeks of the acute event. To classify the syndrome of unresolved pulmonary embolism we reviewed our experience and that of the English literature to extract 30 well-described cases. The mean age at presentation was 45 years, and most patients were less than 60 years old. Almost all complained of dyspnea, and the majority had at least one clinical event suggestive of PE. Most had clinical evidence of pulmonary hypertension. Roentgenographic, arterial blood gas and electrocardiographic findings were nonspecific, though the perfusion lung scan was always abnormal. Most patients exhibited mild-to-moderate pulmonary hypertension. The severity of pulmonary artery obstruction was quite variable and did not correlate with the magnitude of arterial hypoxemia or pulmonary hypertension. Most patients did not improve with long-term anticoagulation therapy and underwent pulmonary embolectomy with acceptable mortality. Postoperative improvement correlated with improved arterial blood gas levels, abatement of pulmonary hypertension, and more satisfactory pulmonary perfusion.

The comparative effects of ionic versus nonionic agents in cardiac catheterization.

Although all contrast media that are used in ventriculography and coronary arteriography have some adverse effects, clinical and laboratory experiences with nonionic contrast media have provided evidence of the lower toxicity and better tolerability associated with these agents. A review of comparative studies of nonionic and ionic contrast media is presented. The nephrotoxic and cardiotoxic effects of ionic contrast agents are discussed. The advantages of the nonionic agent, iohexol, are outlined, and guidelines for its use are suggested.

Acute pharmacodynamics and pharmacokinetics of oral amrinone.

Amrinone was administered orally as a single 100-mg dose to six male patients with moderate-severe congestive heart failure to determine the acute pharmacodynamic effects and pharmacokinetics of the drug. Following right heart catherization and amrinone administration, measurements of hemodynamic parameters including cardiac index (Cl), right atrial pressure (RA), pulmonary capillary wedge pressure (PCW), and serum amrinone concentrations (SAC) were made at hourly intervals for up to 8 hours. Cl increased (29.0 per cent) significantly (P less than 0.05) at 3 hours after dose. PCW declined quickly after dose and was significantly (P less than 0.05) lower (-31.3 per cent) than control at 3 hours. RA declined gradually, and a significant (P less than 0.05) reduction (-25.2 per cent) was achieved 5 hours after the dose. Amrinone was absorbed quickly (tmax = 1.4 hour), and the disappearance of amrinone from serum was log-linear (t1/2 = 5.1 hours). The time courses of per cent change in Cl and SAC were similar, and the correlation between the average per cent change in Cl and average SAC was linear and significant (r = 0.80; P less than 0.05).

The natural history of pulmonary embolism.

It has been found that the proper management of pulmonary embolism improves survival. This article reviews the natural history of pulmonary embolism as it relates to the appropriateness of several alternative therapeutic strategies.

Pharmacokinetics of intravenous bepridil in patients with coronary disease.

The pharmacokinetics of intravenous bepridil (1-[2-(N-benzylanilino)-1-(isobutoxymethyl)ethyl]pyrrolidine ) were studied in 16 patients undergoing cardiac catheterization for evaluation of coronary disease, all with normal base-line hemodynamic and renal functions. Ten patients received 3 mg/kg and six patients received 4 mg/kg of bepridil infused over a period of 30 min. Plasma bepridil concentrations were measured by HPLC and analyzed by model-dependent and model-independent methods. The mean (+/- SD) maximum plasma bepridil concentrations at the end of the infusion were 2047 +/- 820 ng/mL (3 mg/kg) and 2478 +/- 1426 ng/mL (4 mg/kg). Postinfusion bepridil concentrations were best described by a two-compartment open model. The model-dependent harmonic mean distribution and elimination half-lives were 1.7 h (range: 1.1-2.2 h) and 19.7 h (range: 8.0-61.9 h), respectively. The harmonic mean elimination half-life from model-independent analysis was 14.9 h (range: 7.4-64.0 h). The arithmetic means of other model-independent kinetic parameters were systemic clearance, 0.524 +/- 0.215 L X kg-1 X h-1; Vd, 15.3 +/- 10.9 L/kg; and Vdss, 10.1 +/- 6.0 L/kg. Model-dependent and model-independent estimates of half-life and clearance agreed reasonably well. Bepridil was well tolerated, effecting little or no change in central hemodynamics or EKG intervals. The extensive distribution and relatively slow clearance of bepridil account for its long elimination half-life. Intravenous bepridil appears to be a safe calcium (II) antagonist that is suitable for once-a-day dosing.

Cardiac tamponade masking pulmonary embolism.

This report describes a patient admitted with shortness of breath due to cardiac tamponade, which masked concomitant pulmonary embolism that was diagnosed only after right heart pressures failed to decrease after successful pericardiocentesis. The patient was found to have widely metastatic adenocarcinoma of colon (with metastases to pericardium) and a paraneoplastic syndrome of deep vein thrombosis.

Pulmonary angiography in the diagnosis of pulmonary embolism.

In patients in whom there is clinical suspicion of pulmonary thromboembolic disease, because of the risk of inadequate treatment, definitive radiologic evaluation should be carried out. Of the diagnostic procedures available, conventional pulmonary angiography has the greatest sensitivity and specificity in the detection of pulmonary embolism or other pulmonary vascular disease. Pulmonary angiography is indicated for patients with an indeterminate lung scan, for those with a high-probability lung scan in whom confirmation is necessary because of high risk for bleeding complications from anticoagulation, if embolism is massive and embolectomy is contemplated, if thrombolytic therapy or vena cava interruption is considered or if there is significant clinical evidence for an alternative diagnosis as well as for those with low-probability scans with a high degree of clinical suspicion and to complete a workup in patients with pulmonary hypertension. Refinements in the technique have simplified and expanded its application. The hemodynamic evaluation with right-heart catheterization before and after pulmonary angiography plays an important role in the choice of treatment of pulmonary embolism. In patients with multiple bilateral lobar or segmental perfusion defects, performance of right and left pulmonary arteriography in the right and left posterior oblique projections should be carried out. In the presence of additional pulmonary hypertension, the lung in which perfusion is most abnormal is selected first for angiography with a low bolus contrast dose. The angiographic criteria for the diagnosis of pulmonary embolism are intraluminal vascular filling defects or an abrupt cutoff of a large vessel. For selective opacification of lobar pulmonary branches occlusion pulmonary angiography is helpful. The mortality of pulmonary angiography in experienced centers is approximately 0.3%. Complications may include cardiac perforation in up to 1% and subendocardial injury in less than 0.2%. In patients with pulmonary embolism but no pulmonary hypertension, treatment with heparin for ten to 14 days should be followed by coumadin anticoagulation for at least three to six months. For obstruction of greater than or equal to 50% of the pulmonary vascular cross-sectional area and pulmonary hypertension thrombolytic therapy should be given and insertion of an inferior caval filter can be considered. In those with more than 75% pulmonary vascular obstruction and corresponding hemodynamic derangement, pulmonary artery embolectomy or thrombolytic therapy should be carried out.4