James W. Crow

A Comparison of Continuous Intravenous Epoprostenol (Prostacyclin) with Conventional Therapy for Primary Pulmonary Hypertension

BACKGROUND Primary pulmonary hypertension is a progressive disease for which no treatment has been shown in a prospective, randomized trial to improve survival. METHODS We conducted a 12-week prospective, randomized, multicenter open trial comparing the effects of the continuous intravenous infusion of epoprostenol (formerly called prostacyclin) plus conventional therapy with those of conventional therapy alone in 81 patients with severe primary pulmonary hypertension (New York Heart Association functional class III or IV). RESULTS Exercise capacity was improved in the 41 patients treated with epoprostenol (median distance walked in six minutes, 362 m at 12 weeks vs. 315 m at base line), but it decreased in the 40 patients treated with conventional therapy alone (204 m at 12 weeks vs. 270 m at base line; P < 0.002 for the comparison of the treatment groups). Indexes of the quality of life were improved only in the epoprostenol group (P < 0.01). Hemodynamics improved at 12 weeks in the epoprostenol-treated patients. The changes in mean pulmonary-artery pressure for the epoprostenol and control groups were -8 percent and +3 percent, respectively (difference in mean change, -6.7 mm Hg; 95 percent confidence interval, -10.7 to -2.6 mm Hg; P < 0.002), and the mean changes in pulmonary vascular resistance for the epoprostenol and control groups were -21 percent and +9 percent, respectively (difference in mean change, -4.9 mm Hg/liter/min; 95 percent confidence interval, -7.6 to -2.3 mm Hg/liter/min; P < 0.001). Eight patients died during the study, all of whom had been randomly assigned to conventional therapy (P = 0.003). Serious complications included four episodes of catheter-related sepsis and one thrombotic event. CONCLUSIONS As compared with conventional therapy, the continuous intravenous infusion of epoprostenol produced symptomatic and hemodynamic improvement, as well as improved survival in patients with severe primary pulmonary hypertension.

Echocardiographic predictors of adverse outcomes in primary pulmonary hypertension

OBJECTIVES The aim of this study was to evaluate the relationships between echocardiographic findings and clinical outcomes in patients with severe primary pulmonary hypertension (PPH). BACKGROUND Primary pulmonary hypertension is associated with abnormalities of right heart structure and function that contribute to the poor prognosis of the disease. Echocardiographic abnormalities associated with PPH have been described, but the prognostic significance of these findings remains poorly characterized. METHODS Echocardiographic studies, invasive hemodynamic measurements and 6-min walk tests were performed and outcomes prospectively followed in 81 patients with severe PPH. Subjects were participants in a 12-week randomized trial examining the effects of prostacyclin plus conventional therapy compared with conventional therapy alone. RESULTS During the mean follow-up period of 36.9 +/- 15.4 months, 20 patients died and 21 patients underwent transplantation. Pericardial effusion (p = 0.003) and indexed right atrial area (p = 0.005) were predictors of mortality. Pericardial effusion (p = 0.017), indexed right atrial area (p = 0.012) and the degree of septal shift in diastole (p = 0.004) were predictors of a composite end point of death or transplantation. In multivariable analyses incorporating clinical, hemodynamic and echocardiographic variables, pericardial effusion and an enlarged right atrium remained predictors of adverse outcomes. Six-minute walk results, mixed venous oxygen saturation and initial treatment randomization were also independently associated with a poor prognosis. CONCLUSIONS Pericardial effusion, right atrial enlargement and septal displacement are echocardiographic abnormalities that reflect the severity of right heart failure and predict adverse outcomes in patients with severe PPH. These characteristics may help identify patients appropriate for more intensive medical therapy or earlier transplantation.

Treatment of Primary Pulmonary Hypertension with Continuous Intravenous Prostacyclin (Epoprostenol): Results of a Randomized Trial

STUDY OBJECTIVE To determine the efficacy of continuous intravenous infusion of prostacyclin (epoprostenol) in primary pulmonary hypertension. DESIGN Randomized trial with 8-week treatment periods and nonrandomized treatment for up to 18 months. SETTING Four referral centers. PATIENTS Sequential sample of 24 patients with primary pulmonary hypertension. Nineteen patients completed the study. Four patients died and one left the study because of adverse effects (pulmonary edema). INTERVENTIONS Continuous intravenous prostacyclin administered by portable infusion pump at doses determined by acute responses during baseline catheterization in ten patients. Nine patients were treated with anticoagulants, oral vasodilators, and diuretics. MEASUREMENTS AND MAIN RESULTS Starting with a baseline value for total pulmonary resistance of 21.6 units, there was a decrease of 7.9 units (95% CI, -13.1 to -2.2; P = 0.022) in the prostacyclin-treated group after 8 weeks; there was virtually no change in the conventional therapy group (from 20.6 to 20.4 units, not significant). Six of ten prostacyclin-treated patients who completed the 8-week study period had reductions in mean pulmonary artery pressure of greater than 10 mm Hg, whereas only one of nine in the conventional treatment group had a similar response (P = 0.057). Nine patients receiving prostacyclin for up to 18 months have persistent hemodynamic effects, although dose requirements have increased with time. Complications have been attributable to the drug delivery system. CONCLUSIONS Prostacyclin produces substantial and sustained hemodynamic and symptomatic responses in severe primary pulmonary hypertension and may be useful in the management of some patients with this disease.

Effects of Long-term Infusion of Prostacyclin (Epoprostenol) on Echocardiographic Measures of Right Ventricular Structure and Function in Primary Pulmonary Hypertension

Background Right heart failure is an important cause of morbidity and mortality in primary pulmonary hypertension. In a recent prospective, randomized study of severely symptomatic patients, treatment with prostacyclin (epoprostenol) produced improvements in hemodynamics, quality of life, and survival. This article describes the echocardiographic characteristics of participants in this trial; the relationships of echocardiographic variables to hemodynamic parameters, exercise capacity, and quality of life; and the echocardiographic changes associated with prostacyclin therapy. Methods and Results The 81 patients enrolled in this multicenter trial were randomized to treatment with a long-term infusion of prostacyclin in addition to conventional therapy (n=41) or conventional therapy alone (n=40) for 12 weeks. Echocardiograms and assessments of hemodynamics, exercise capacity, and quality of life were performed before and after the treatment phase. On baseline evaluation, patients had marked right ventricul...

Hemodialysis Using Prostacyclin Instead of Heparin as the Sole Antithrombotic Agent

Anticoagulation during hemodialysis is necessary to prevent clotting of the blood on contact with the dialysis membrane. Heparin is the usual anticoagulant used, but systemic anticoagulation may persist for hours, and hemorrhage is common. We successfully used an infusion of prostacyclin, which has an in vitro half-life of three to five minutes, as the sole anticoagulant in 10 patients on long-term hemodialysis and in one patient undergoing dialysis for acute renal failure (this patient bled severely on three occasions when heparin was used). Prostacyclin was infused intravenously for 10 minutes before dialysis and into the arterial line of the dialyzer during dialysis. We adjusted the rate of infusion into the dialyzer to prevent prostacyclin-induced hypotension. Each patient completed 240 minutes of dialysis and received a total of 423 +/- 91 ng of prostacyclin per kilogram of body weight (mean +/- S.E.M.; range, 56 to 780). Prostacyclin caused no clinically important changes in the intrinsic clotting system, and there were no hemorrhages or clotting of the coil. We conclude that prostacyclin can safely replace heparin as the sole antithrombotic agent during hemodialysis and may be more advantageous if anticoagulation is contraindicated.

Prostacyclin substitution for heparin in long-term hemodialysis

We studied prostacyclin as a substitute for heparin in 12 patients who underwent maintenance hemodialysis. All subjects underwent initial hemodialysis with prostacyclin as the sole anticoagulant; 10 of the 12 were restudied during heparin hemodialysis. Few adverse reactions occurred during prostacyclin hemodialysis in the 10 patients in whom dialysis was performed against a bicarbonate-containing dialysate; however, significant hypotension developed in two subjects when an acetate bath was used. Platelet aggregation progressively decreased during prostacyclin hemodialysis (p less than 0.02), but not during heparin hemodialysis, and returned toward control values after hemodialysis. Platelet thromboxane release decreased during both prostacyclin and heparin hemodialysis. Intradialytic percent decrements in serum urea nitrogen and creatinine were greater during prostacyclin than heparin administration (42 +/- 2.9 percent versus 36 +/- 2.6 percent [p less than 0.05] and 33 +/- 2.6 percent versus 29 +/- 2.1 percent [0.05 less than p less than 0.1], respectively). The plasma concentrations of 6-keto-prostaglandin-F1 alpha, a prostacyclin metabolite, reached peak levels by 120 minutes of hemodialysis and declined biexponentially toward predialysis concentrations during 120 minutes after hemodialysis, thereby providing an index of cumulative prostacyclin dosage. We conclude that prostacyclin is not only a safe alternative to heparin anticoagulation during hemodialysis, but that prostacyclin might also increase the efficiency of hemodialysis.

Frequency and Severity of Tricuspid Regurgitation Determined by Doppler Echocardiography in Primary Pulmonary Hypertension

W previously described a high prevalence of functional tricuspid regurgitation (TR) in patients with severely symptomatic primary pulmonary hypertension (PPH).1 We report the relations of TR to right ventricular (RV) size and geometry, tricuspid annulus diameter, tricuspid leaflet displacement, hemodynamics, and exercise capacity in these patients. • • • The study group consisted of 78 patients enrolled in a multicenter trial of epoprostenol (Flolan, GlaxoSmithKline, Research Triangle Park, North Carolina) for the treatment of severe PPH.2 The study consisted of 56 women and 32 men (mean age 40 15 years). Most (74%) had New York Heart Association class III symptoms; their average mean pulmonary arterial pressure was 60 12 mm Hg. All participants met the criteria for PPH as defined by the National Institutes of Health Patient Registry,3 and all had New York Heart Association class III or class IV symptoms. The study was approved by the institutional review committee of each participating center, and informed consent was acquired from each patient before enrollment. Baseline echocardiograms of all participants were obtained using a defined imaging protocol and recorded on videotape. All studies were analyzed using an off-line quantification system by a single observer from the core echocardiographic laboratory. Measurements were obtained on 3 representative beats, and the results averaged. Details of the imaging and quantification protocols, including reproducibility data, have been described previously.1 The severity of TR was determined from 2-dimensional and Doppler color flow images in the apical 4-chamber view. Frame-by-frame analysis of each cardiac cycle was used to identify the maximum area of the Doppler color flow jet. The outline of the regurgitant signal, including aliased signals and contiguous velocities moving in the same direction, was traced and the area determined by computerized planimetry. The area of the right atrium was similarly measured on the same frame. The severity of TR was quantified as the ratio of the Doppler regurgitant jet area to the right atrial (RA) area (the TR/RA ratio). Previous investigators have demonstrated that this ratio is correlated closely with the severity of TR measured by a double thermodilution technique.4 Severe TR was defined as a TR/RA ratio 0.34, a ratio that corresponds to severe TR as judged by thermodilution4 or intraoperative digital palpation.5 TR was considered moderate if the TR/RA ratio was 0.20 and 0.34, and mild if the TR/RA ratio was 0.20. The tricuspid valve was examined in the apical 4-chamber view for thickening or doming, and for abnormal closure. The apical displacement of the tricuspid leaflets, an index of abnormal closure due to chordal tension, was measured as the distance from the coaptation point to the plane of the tricuspid annulus at the time of maximal systolic closure. Loss of coaptation was defined as a visible separation of the septal and anterior leaflets throughout systole. The following echocardiographic measures of RV structure were obtained in the apical 4-chamber view at end-diastole and at end-systole. (1) The tricuspid annulus diameter was measured from the point of attachment of the septal leaflet to the attachment of the anterior leaflet. This diameter was corrected for differences in body size by dividing by height. (2) The RV remodeling index was calculated as the ratio of RV short and long axes; the short axis was defined as the distance between the septal and free wall endocardial surfaces of the right ventricle at the midventricular level. The long axis was measured from the endocardial surface at the tip of the RV apex to the midpoint of the annular plane. (3) RV area was measured by planimetry, tracing the endocardial edge of the right ventricle and the plane of the tricuspid valve, and corrected for height. From the Department of Medicine, University of North Carolina, Chapel Hill, North Carolina; University of Washington, Seattle, Washington; Maine Medical Center, Portland, Maine; Washington University, St. Louis, Missouri; Rhode Island Hospitals, Providence, Rhode Island; Louisiana State Medical Center, New Orleans, Louisiana; Cato Research Ltd., Durham, North Carolina; Department of Biostatistics, University of North Carolina, Chapel Hill, North Carolina; GlaxoSmithKline, Research Triangle Park, North Carolina; and United Therapeutics Inc., Chapel Hill, North Carolina. This study was supported by Burroughs Wellcome Co., Research Triangle Park, North Carolina. Dr. Hinderliter’s address is: Division of Cardiology, University of North Carolina, CB 7075, Chapel Hill, North Carolina, 27599. E-mail: hinderli@med.unc.edu. Manuscript received July 29, 2002; revised manuscript received and accepted December 20, 2002.

Safety and Efficacy of Epoprostenol in Patients with Severe Congestive Heart Failure

Patients with advanced heart failure often remain severely symptomatic and have a high mortality rate despite currently available therapy. We studied the safety and efficacy of a new approach to the patient with refractory heart failure: continuous intravenous treatment via a portable infusion pump with epoprostenol (prostacyclin), a potent pulmonary and systemic vasodilator. A group of 33 patients with severe heart failure (64% New York Heart Association class IV and 36% class III) and profound ventricular dysfunction (median left ventricular ejection fraction, 0.15)--despite prior treatment with diuretics (100%), digitalis (91%), angiotensin-converting enzyme inhibitors (85%), and dobutamine (30%)--underwent a baseline 6-minute walk test prior to dose titration with epoprostenol during invasive hemodynamic monitoring. Subjects responding during the dose titration were randomized, on an open basis, to receive either continuous epoprostenol infusion via an indwelling central venous catheter plus conventional therapy or conventional therapy alone for 12 weeks. The initial dose-ranging study with epoprostenol produced a significant decline in systemic and pulmonary vascular resistance and a substantial increase in cardiac index despite a fall in pulmonary capillary wedge pressure. Symptoms related to vasodilation were noted within the first week after randomization to epoprostenol in 9 of 16 patients but resolved with adjustment of the infusion and concomitant medications in all but one subject. Dose adjustments during the chronic epoprostenol infusion were infrequent after the first week and complications related to the drug delivery system were rare. The change in distance walked from baseline to the last available 6-minute walk test was significantly greater in patients who received epoprostenol compared with patients assigned to standard therapy (72 +/- 40 vs -39 +/- 32 m, mean +/- SEM; p = 0.033). Our study suggests that long-term intravenous infusion of epoprostenol is feasible in patients with severe heart failure and our hemodynamic and functional results suggest clinical benefit as well. However, until recent results indicating an adverse effect of epoprostenol on survival are fully evaluated, the role of this drug in the treatment of advanced heart failure will remain uncertain.

Epoprostenol (PGI2, prostacyclin) during high-risk hemodialysis: preventing further bleeding complications.

The frequency of hemodialysis‐associated hemorrhage was studied prospectively in two successive, parallel, heparin‐controlled studies using epoprostenol (PGI2; average dose, 4.1 ng/kg‐min) as the sole antithrombotic agent. Sixty‐three patients with active or recently active Weeding underwent 163 hemodialysis treatments in each of which prospective Weeding risk was assessed. PGI2 was associated with up to 50% overall reduction in the frequency of Weeding, particularly in the highest risk circumstances. PGI2 also allowed successful completion of the full, prospectively prescribed hemodialysis time in the most treatments (82% versus 93% with heparin). Furthermore, the efficiency of hemodialysis using PG12, as indicated by the reduction in concentration of blood urea nitrogen and serum creatinine, was equal to that using heparin, even though there was a tendency toward modest reduction in residual volume of the hollow fiber dialyzer and slightly more frequent early termination of treatment from dialyzer clotting with PGI2. No severe vasodilatory side effects of PGI2 were observed during these studies. Hypotension was equally frequent during hemodialysis with heparin as with PGI2. The current results suggest that PGI2 should be considered as a substitute for heparin during high‐risk hemodialysis because PGI2 may reduce the incidence of dialysis‐associated Weeding without severe adverse side effects.

Pitfalls and valid approaches to pharmacokinetic analysis of mean concentration data following intravenous administration

Pharmacokinetic analysis of arithmetic mean concentration data can lead to selection of an inappropriate deterministic compartmental model and biased pharmacokinetic parameter estimates. The terminal phase disposition rate constant estimated by fitting a deterministic model to mean data is in all cases an underestimate of the expected value of this rate constant. The area under the mean data curve calculated via the linear trapezoidal rule from time zero to the last detectable concentration sampling point is equal to the mean of the individual subject areas under the curve for the same time span. This equality supports the use of mean data for determination of model-independent pharmacokinetic parameters.