Chest ACCP Education Calendar
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

Guest Access | Sign In via User Name/Password
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF) Free
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Article Archive
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via ISI Web of Science (21)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Torre-Amione, G.
Right arrow Articles by Pratt, C.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Torre-Amione, G.
Right arrow Articles by Pratt, C.
(Chest. 2001;120:460-466.)
© 2001 American College of Chest Physicians

A Pilot Safety Trial of Prolonged (48 h) Infusion of the Dual Endothelin-Receptor Antagonist Tezosentan in Patients With Advanced Heart Failure*

Guillermo Torre-Amione, MD, PhD; Jean-Bernard Durand, MD; Sheriff Nagueh, MD; Mary T. Vooletich, RN; Isaac Kobrin, MD and Craig Pratt, MD

* From the Winter Center for Heart Failure Research and the Eugene and Judith Campbell Laboratories for Cardiac Transplantation Research (Drs. Torre-Amione, Durand, Nagueh, and Pratt and Ms. Vooletich), Methodist Hospital and Houston VA Medical Center, Baylor College of Medicine, Houston, TX; and Actelion, Ltd (Dr. Kobrin), Allschwil, Switzerland.

Correspondence to: Guillermo Torre-Amione, MD, PhD, Baylor College of Medicine, Section of Cardiology, Texas Medical Center, One Baylor Plaza, Houston, TX 77030; e-mail: gtorre{at}bcm.tmc.edu


   Abstract
TOP
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 Conclusion
 References
 
Study objectives: Tezosentan, an IV dual endothelin-receptor antagonist, has demonstrated beneficial hemodynamic effects in patients with advanced heart failure. In addition, no notable differences in safety and tolerability variables were detected between tezosentan-treated and placebo-treated patients when infused over 4 to 6 h. The present study was conducted primarily to assess the safety and tolerability of tezosentan when administered over a prolonged, 48-h treatment period, and secondarily to investigate hemodynamic response.

Design: This randomized, double-blind, active-controlled study of continual IV administration of two dosages of tezosentan (20 mg/h and 50 mg/h; n = 6 each) or dobutamine (5 µg/kg/min; n = 2) over 48 h in patients with advanced heart failure was conducted to assess tolerability, safety, and hemodynamic variables (Doppler echocardiography).

Results: During tezosentan infusion, no episodes of hypotension requiring withdrawal of therapy occurred, and hemodynamic rebound was not observed after abrupt cessation of the infusion. There were no reports of worsening heart failure in tezosentan-treated patients up to 28 days following the infusion. The most common side effect during the infusion was headache (9 of 12 tezosentan-treated patients and both dobutamine-treated patients). Echocardiographic Doppler measurements suggested improvements in cardiac index, pulmonary capillary wedge pressure, and relaxation properties as well as in diastolic and systolic function in all treatment groups.

Conclusions: Prolonged, 48-h IV dual endothelin-receptor antagonism with tezosentan was well tolerated with no new safety concerns emerging. These data further support the potential role of tezosentan in the treatment of patients with acute heart failure.

Key Words: endothelins • heart failure • pharmacologic therapy


   Introduction
TOP
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 Conclusion
 References
 
Patients with acute heart failure continue to have a poor prognosis despite some success with current pharmacologic therapies. Diuretics, vasodilators, positive inotropes, and inodilators, whether used as single agents or in combination, can improve both hemodynamics and symptomatology in these patients.1 2 3 4 However, they can also cause symptomatic hypotension,5 significant ischemia, an increased incidence of arrhythmia,6 and an induction of tolerance.7 For these reasons, new and novel agents for the treatment of heart failure continue to be developed.

Considerable evidence has accumulated implicating the endothelin (ET) system in various cardiovascular disease states, including congestive heart failure (CHF).8 ET-1 is a potent vasoconstrictor/mitogenic peptide of endothelial origin that mediates its effects via both ET-A and ET-B receptor subtypes.9 Both the effects of ET-1 and the tissue distribution of the two known receptors (endothelium, vascular smooth muscle, and cardiac fibroblasts, among others) support a role for the ET system in heart failure.9 10 11 Data12 from animal models of heart failure demonstrate that interventions that reduce the activity of the ET system improve hemodynamic parameters. In heart failure patients, two studies13 14 in which the biological effects of ET-1 were antagonized with short-term treatment with an oral ET-A/ET-B–receptor antagonist, bosentan, support the notion that blockade of ET-1 activity exerts beneficial hemodynamic effects.

Tezosentan (Ro 61–0612) is a dual endothelin-receptor antagonist specifically developed for parenteral use in acute cases when a rapid onset of action is required. Tezosentan is water soluble, allowing IV administration, and has a short first apparent elimination half-life of about 10 min that facilitates rapid titration of its effects.15 In both animals and humans, its metabolism is limited and excretion is primarily through the bile as the unchanged compound. In several animal models of heart failure, ischemic renal failure, and hypertension, tezosentan was found to be pharmacologically active with a rapid onset of action.15

Two previous placebo-controlled phase II studies16 17 of tezosentan in patients with moderate-to-severe heart failure have demonstrated that short-term (4 to 6 h) infusions of dosages ranging from 5 to 100 mg/h were safe and well tolerated. Invasive hemodynamic measurements showed tezosentan to have a significant beneficial effect on both preload and afterload, the majority of which was achieved with the 20-mg/h and 50-mg/h dosages. Beneficial effects were achieved without increases in heart rate or incidence of arrhythmia. In preparation for phase III trials in patients with acute heart failure, the present study was conducted to determine if prolonged, 48-h infusion of tezosentan continued to be safe and well tolerated. Noninvasive Doppler echocardiography and global clinical assessments were used to investigate effects on cardiac function and patient well being.


   Materials and Methods
TOP
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 Conclusion
 References
 
This was a randomized, double-blind, active-controlled, parallel-group study of the IV administration of two dosages of tezosentan, or dobutamine, with assessments of tolerability, safety, cardiac function, and global improvement. The use of an active control drug was primarily selected as a common and appropriate therapy to blind both investigators and patients to treatment assignment. The study was conducted at a single center in the United States (Baylor College of Medicine, Houston, TX). The institutional ethics committee approved the study protocol, and all patients provided written informed consent.

Patients
The study population included male and female patients (postmenopausal, surgically sterile, or receiving contraceptives) at least 18 years of age with symptomatic New York Heart Association (NYHA) class III to IV CHF due to ischemic heart disease or dilated cardiomyopathy. Inclusion requirements were a left ventricular ejection fraction < 35% within the last year, and currently receiving established medications for CHF that included a diuretic and an angiotensin-converting enzyme (ACE) inhibitor unless intolerance or contraindication could be documented. The use of digitalis or vasodilators was allowed but not mandatory. Patients were excluded from the study if they needed IV therapy for heart failure within 7 days prior to the study or had severe hypertension, clinically significant hypotension (sitting systolic BP < 85 mm Hg), myocardial infarction within the last 4 weeks, unstable angina, hemodynamically relevant cardiac arrhythmias, or other serious systemic diseases.

Protocol
Qualified patients were randomized in a 3:3:1 ratio to receive tezosentan 20 mg/h, tezosentan 50 mg/h, or dobutamine 5 µg/kg/min, all administered IV at 8 mL/h for 48 h. The infusion rate could be decreased by half once or twice if systolic BP fell below 80 mm Hg but could not be increased. Background treatments for heart failure were administered as usual on the days of study treatment. However, drugs that might interfere with the effects of tezosentan (eg, calcium channel blockers, sympathomimetics, injectable diuretics, short-acting inhaled and IV nitrate derivatives, phosphodiesterase inhibitors, and injectable antiarrhythmics) were not administered for 7 days prior to the start of the infusion and on the days of study treatment. Patients were monitored continuously by ECG, and the study did not require stays in the ICUs.

During the 48-h infusion, vital signs were measured periodically and adverse events were monitored continuously. Twelve-lead ECGs were performed before and after drug infusion. Blood and urine samples were obtained for clinical laboratory tests at screening and at the end of infusion. Patients were followed up for adverse events 24 h after the end of treatment. Patients were again contacted 28 days after the end of the infusion to follow up any adverse events that were ongoing at hospital discharge and to record new serious adverse events and death.

After screening, 12 of the 14 hospitalized patients underwent Doppler echocardiography just before the start of the infusion and again just after the infusion. Stroke volume, cardiac index, pulmonary capillary wedge pressure (PCWP), right atrial pressure (RAP), systolic pulmonary artery pressure (PAP), diastolic PAP, mitral inflow with the ratio of the amplitudes of the waves created by early diastolic filling and atrial contraction, and deceleration time of early diastolic filling velocity were determined. Each patient’s clinical status was independently evaluated by the investigator and the patient after 48 h of infusion using a 7-point scale (much better, moderately better, slightly better, unchanged, slightly worse, moderately worse, and much worse).

Analyses
The primary safety parameter of the study was the incidence of adverse events; secondary safety parameters included ECGs, clinical laboratory tests, and vital signs. Because of the small numbers of patients in each group, all safety data were analyzed descriptively. Cardiac index was calculated as cardiac output/body surface area. Echocardiography results from all tezosentan-treated patients were combined and analyzed descriptively, with the p value for change from baseline determined by the Student’s t test. Global assessments of clinical status were also analyzed descriptively, with the seven categories for global assessments collapsed into three categories (better, unchanged, worse).


   Results
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 Conclusion
 References
 
Patient Characteristics
The 14 recruited patients were randomized to receive tezosentan at 20 mg/h (n = 6), tezosentan at 50 mg/h (n = 6), or dobutamine at 5 µg/kg/min (n = 2). No patients were prematurely withdrawn from the study, and all patients were considered evaluable. The patient population consisted of nearly equal numbers of men and women, was primarily African American (71%), and had a wide age range (25 to 73 years; Table 1 ). All but one patient were classified as having NYHA class III, and similar numbers in each group had CHF due to ischemic disease and dilated cardiomyopathy. Ejection fractions ranged from 18 to 35%. The two patients in the dobutamine group were older, and both were African American. All patients were receiving concomitant medications for CHF (Table 2 ). In the tezosentan 50-mg/h group, one patient was not receiving an ACE inhibitor (documented intolerance) or angiotensin II-receptor blocker, one patient was not receiving a diuretic, and only one patient was not receiving digoxin (not required).


View this table:
[in this window]
[in a new window]

  		Table 1.. Demographics and Baseline Disease Characteristics*

 

View this table:
[in this window]
[in a new window]

  		Table 2.. Concomitant Treatments for CHF*

 
Hemodynamic and Clinical Effects
Assessment of hemodynamics by Doppler echocardiography demonstrated that cardiac index and stroke volume increased whereas PCWP, RAP, systolic PAP, and diastolic PAP decreased in all treatment groups after the 48-h infusion (Table 3 ). Among the small number of patients in this study, there was no apparent dose-effect relationship, and all tezosentan-treated patients were combined for presentation. In the combined population, significant (p <= 0.026) changes from baseline were observed for all but the diastolic PAP (Table 3) . The increase (p < 0.01) in the deceleration time of early diastolic filling velocity with tezosentan treatment suggested improvement in diastolic function. The patient’s global clinical status was independently judged as improved by both the physician and patient for all but two patients in the tezosentan 50-mg/h group. For each of these two patients, the physician and patient disagreed; one patient was considered slightly improved (ie, unchanged) by the physician and moderately improved (ie, improved) by the patient, and the other moderately improved by the physician and slightly improved by the patient.


View this table:
[in this window]
[in a new window]

  		Table 3.. Changes in Hemodynamic Variables After 48 h of Tezosentan Infusion*

 
Safety
Adverse events were common in the study population. All but one patient (tezosentan at 20 mg/h) reported an adverse event during the infusion or the day following (Table 4 ). Headache was the most common adverse event for all treatment groups (including dobutamine), occurring in 11 of the 14 patients in the study. Headache did not appear to be dose related, in most cases was of no more than 1 day in duration, and in no case was severe. Most other adverse events occurred in single patients and were considered mild. Two patients receiving tezosentan at 20 mg/h had asymptomatic mild hypotension, transient in one patient and requiring a temporary decrease in the infusion rate in the other patient. There were no cases of hypotension in the tezosentan 50-mg/h group. One patient in the tezosentan 50-mg/h group reported moderate nausea and vomiting during infusion. In the 20-mg/h tezosentan group, mild nausea and vomiting occurred in one patient whose infusion rate was inadvertently increased to 11 mL/h. These symptoms resolved when the infusion rate was returned to 8 mL/h. Mild nausea was reported for another patient in the tezosentan 20-mg/h treatment group on day 4 (>= 12 h after the end of the infusion).


View this table:
[in this window]
[in a new window]

  		Table 4.. Summary of Adverse Events*

 
There were no deaths during the study, and a single patient reported two serious adverse events; pulmonary embolism was diagnosed in this patient (tezosentan at 50 mg/h) on day 15 (12 days after the end of treatment infusion). On day 29 of the study, the same patient was suspected of having recurrent pulmonary embolism. In both instances, the investigator considered the event unrelated to trial treatment.

Treatment-emergent ECG findings occurred in five patients, but they were expected findings in this patient population and revealed no obvious treatment-related concern or dose-related finding. Left atrial enlargement was the only ECG change that occurred in more than one patient in the study (two patients in the tezosentan 20-mg/h group). No evidence of significant arrhythmias was observed on continuous telemetry during the infusion. Small mean changes in pathologic Q wave, QRS complex, and QT intervals occurred in all treatment groups, with no obvious pattern or clinical relevancy.

Mean pulse rates changed little during the 48-h treatment period in both tezosentan treatment groups (Fig 1 , top, A; Table 5 ). There were small decreases in both systolic and diastolic BPs in both tezosentan groups that appeared to be dose related at the end of infusion (Table 5) . However, a dose relationship was not readily apparent over the course of the 48-h treatment (Fig 1 , middle, B, and bottom, C).



View larger version (19K):
[in this window]
[in a new window]
[Download PPT slide]
  		Figure 1.. Time course of tezosentan treatment effect on (top, A) pulse rate, (middle, B) systolic BP, and (bottom, C) diastolic BP. Values are mean ± SE change from baseline. Filled circles = tezosentan at 20 mg/h, n = 6; open circles = tezosentan at 50 mg/h, n = 6; squares = dobutamine at 5 µg/kg/min, n = 2.

 

View this table:
[in this window]
[in a new window]

  		Table 5.. Change in Vital Signs From Baseline to End of Treatment*

 
There were no clinically relevant changes for most laboratory values and no discernible differences among treatments. Small decreases (<= 8.5%) in hemoglobin, hematocrit, and RBC values were observed in the tezosentan 50-mg/h group that were not seen in the 20-mg/h group.


   Discussion
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
Conclusion
 References
 
The results of this study demonstrated that at pharmacologically active dosages, tezosentan was safe and well tolerated when administered as a 48-h infusion to patients with advanced heart failure. The changes in Doppler echocardiographic variables indicated hemodynamic improvement in the tezosentan groups consistent with those in previous tezosentan trials.16 17 The increases observed in stroke volume, cardiac index, and deceleration time of early diastolic filling velocity were accompanied by decreases in PCWP, RAP, and systolic and diastolic PAPs. And as in previous studies, there was no increase in heart rate, indicating that the beneficial effects of tezosentan were not due to a chronotropic effect. In association with the improvement in hemodynamics, there was good correlation between physician and patient in assessments of symptomatic improvement for most patients. These effects confirm findings in short-term studies16 17 and provide data on a largely (70%) African American patient population.

As tezosentan was designed for the treatment of acute heart failure, it is important that prolonged infusions be safe and well tolerated. The safety data on 48-h infusions from the present study are in agreement with the findings of earlier trials16 17 in patients with advanced heart failure where tezosentan was administered at varying dosages for durations of 4 h or 6 h. In these placebo-controlled studies, no notable differences were detected in safety and tolerability variables between tezosentan-treated and placebo-treated patients. Uniformly, there were no episodes of ventricular tachycardia or symptomatic hypotension requiring drug therapy termination. Although plasma concentrations of ET-1 were increased with tezosentan infusion, hemodynamic rebound was not observed after abruptly stopping tezosentan infusions. Beneficial hemodynamic effects were maintained with a gradual return toward baseline values over a 4-h period, and there were no reports of worsening heart failure in tezosentan-treated patients. In the present study, no new safety concerns emerged with the longer duration of infusion. The most common side effect during the 48-h tezosentan infusion was headache, and there were no significant changes in ECG parameters, liver function test results, or any other biochemical parameter. Nausea and vomiting occurred rarely. Neither the frequency nor the severity of hypotension increased with the longer tezosentan infusions. Two patients in the 20-mg/h group had asymptomatic hypotension without associated increases in heart rate; one case was transient and the other patient was successfully treated with a temporary reduction in the infusion rate. No cases of hypotension occurred in the 50-mg/h group; therefore, no dose relationship was observed.

Recent investigations18 19 20 indicate that abnormalities in left ventricular diastolic distensibility in addition to systolic dysfunction may contribute to symptoms of CHF in many patients. In order to investigate cardiac diastolic function, noninvasive Doppler echocardiographic measurements were included in the study. Pulsed Doppler echocardiography complements two-dimensional imaging for assessment of left ventricular filling properties that are often altered with diastolic dysfunction.21 22 Using this technique, we found that along with the decrease in the filling pressures, there was a prolongation of the deceleration time of the early diastolic filling velocity. This finding is consistent with the beneficial effect on left ventricular filling pressures and is also suggestive of improved diastolic function after tezosentan administration. These data are important because heart failure patients with normalized diastolic function following aggressive intervention are at lower risk of death than are those in whom diastolic function remains abnormal.23 It is conceivable that tezosentan may have unique properties that in addition to improving hemodynamic function may also improve diastolic function.

ET-receptor antagonists represent a novel therapeutic approach to a fundamental and newly discovered endogenous vasoconstrictor mechanism. However, knowledge about the contribution of each receptor subtype to the deleterious effects of excess ET-1 in patients with heart failure is evolving and will have important implications for the usefulness and limitations of ET-receptor blockade. While preliminary trials13 14 16 have demonstrated beneficial hemodynamic effects with interventions that reduce the activity of the ET system, concerns regarding the safety of ET-receptor antagonism remain. Differential roles for ET-A and ET-B receptors in vasoconstriction and vasodilation, respectively, have led to controversy about single receptor-targeted vs dual receptor-targeted therapies. Moreover, both receptors are found in many tissues, and the consequences of blockade at nontarget sites are unknown. Since blockade of these receptors results in an increase in circulating ET-1, there is concern that stopping therapy will result in rebound vasoconstriction and worsening of heart failure. In this study, there was no evidence for such a rebound effect even with prolonged tezosentan infusion, consistent with results in the previous two short-term studies in this patient population.16 17 The safety profile and hemodynamic effects of tezosentan appear to fulfill many of the sought-after characteristics of therapy, but larger studies in patients with acute need for treatment are required to determine this definitively.


   Conclusion
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Conclusion
References
 
In the present study, continual infusions of tezosentan at 20 mg/h and 50 mg/h were well tolerated for 48 h. No new safety concerns emerged with the longer duration of infusion, and pharmacodynamic data indicated an improvement in patient conditions. Larger randomized studies are needed to establish whether dual ET antagonism has beneficial clinical effects and is capable of improving survival and/or symptoms in acute heart failure patients.


   Footnotes
 
Abbreviations: ACE = angiotensin-converting enzyme; CHF = congestive heart failure; ET = endothelin; NYHA = New York Heart Association; PAP = pulmonary arterial pressure; PCWP = pulmonary capillary wedge pressure; RAP = right atrial pressure

This study was supported by a grant from Actelion, Ltd., Allschwil, Switzerland.

Received for publication September 25, 2000. Accepted for publication February 14, 2001.


   References
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Conclusion
 References
 

  1. . Heart Failure Society of America. (1999) Heart Failure Society of America (HFSA) practice guidelines: HFSA guidelines for management of patients with heart failure caused by left ventricular systolic dysfunction; pharmacologic approaches. J Card Fail 5,357-382[CrossRef][ISI][Medline]
  2. . Agency for Health Care Policy and Research (1998) Heart failure: evaluation and treatment of patients with left ventricular systolic dysfunction. J Am Geriatr Soc 46,525-529[ISI][Medline]
  3. Stevenson, L (1998) Inotropic therapy for heart failure. N Engl J Med 339,1848-1850[Free Full Text]
  4. Coodley, E (1999) Newer drug therapy for congestive heart failure. Arch Intern Med 159,1177-1183[Abstract/Free Full Text]
  5. Lindenfeld, J, Lowes, B, Bristow, M (1999) Hypotension with dobutamine: ß-adrenergic antagonist selectivity at low doses of carvedilol. Ann Pharmacother 33,1266-1269[Abstract]
  6. Parmley, W (1987) Factors causing arrhythmias in chronic congestive heart failure. Am Heart J 114,1267-1272[CrossRef][ISI][Medline]
  7. Elkayam, U, Kulick, D, McIntosh, N, et al (1987) Incidence of early tolerance to hemodynamic effects of continuous infusion of nitroglycerin in patients with coronary artery disease and heart failure. Circulation 76,577-584[Abstract/Free Full Text]
  8. Love, M, McMurray, J (1996) Endothelin in chronic heart failure: current position and future prospects. Cardiovasc Res 31,665-674[CrossRef][ISI][Medline]
  9. Summer, M, Cannon, T, Mundin, J, et al (1992) Endothelin ETA and ETB receptors mediate vascular smooth muscle contraction. Br J Pharmacol 107,858-860[ISI][Medline]
  10. Ohlstein, E, Douglas, S (1993) Endothelin-1 modulates vascular smooth muscle structure and vasomotion: implications in cardiovascular pathology. Drug Dev Res 29,108-128[CrossRef][ISI]
  11. Katwa, L, Guarda, E, Weber, K (1993) Endothelin receptors in cultured adult rat cardiac fibroblasts. Cardiovasc Res 27,2125-2129[Abstract/Free Full Text]
  12. Sakai, S, Miyauchi, T, Kobayashi, M, et al (1996) Inhibition of myocardial endothelin pathway improves long-term survival in heart failure. Nature 384,353-355[CrossRef][Medline]
  13. Kiowski, W, Sütsch, G, Hunziker, P, et al (1995) Evidence for endothelin-1-mediated vasoconstriction in severe chronic heart failure. Lancet 346,732-736[CrossRef][ISI][Medline]
  14. Sütsch, G, Kiowski, W, Yan, XW, et al (1998) Short-term oral endothelin-receptor antagonist therapy in conventionally treated patients with symptomatic severe chronic heart failure. Circulation 98,2262-2268[Abstract/Free Full Text]
  15. Clozel, M, Ramuz, H, Clozel, J, et al (1999) Pharmacology of tezosentan, new endothelin receptor antagonist designed for parenteral use. J Pharmacol Exp Ther 290,840-846[Abstract/Free Full Text]
  16. Torre-Amione, G, Young, JB, Durand, J, et al (2001) Hemodynamic effects of tezosentan, an intravenous dual endothelin receptor antagonist, in patients with class III to IV congestive heart failure. Circulation 103,973-980[Abstract/Free Full Text]
  17. Schalcher, C, Mandinov, L, Schindler, R, et al (2000) Dose dependency of hemodynamic changes to the endothelin-receptor antagonist tezosentan in patients with heart failure [abstract]. Eur Heart J 21(suppl),116[Abstract/Free Full Text]
  18. Pouleur, H, Rousseau, MF, van Eyll, C, et al (1993) Cardiac mechanics during development of heart failure: SOLVD Investigators. Circulation 87,IV14-IV20
  19. Brutsaert, DL, Sys, SU, Gillebert, TC (1993) Diastolic failure: pathophysiology and therapeutic implications [published erratum appears in J Am Coll Cardiol 1993; 22:1272] J Am Coll Cardiol 22,318-325[Abstract]
  20. Stainback, RF (1999) Congestive heart failure arising from diastolic dysfunction in the presence of normal left-ventricular systolic function. Tex Heart Inst J 26,34-41[ISI][Medline]
  21. Waggoner, AD (2000) Congestive heart failure and the role of two-dimensional Doppler echocardiography: a primer for cardiac sonographers. J Am Soc Echocardiogr 13,157-163[ISI][Medline]
  22. Nagueh, SF (1999) Noninvasive evaluation of hemodynamics by Doppler echocardiography. Curr Opin Cardiol 14,217-224[CrossRef][ISI][Medline]
  23. Pinamonti, B, Zecchin, M, Di Lenarda, A, et al (1997) Persistence of restrictive left ventricular filling pattern in dilated cardiomyopathy: an ominous prognostic sign. J Am Coll Cardiol 29,604-612[Abstract]



This article has been cited by other articles:


Home page
 The Annals of PharmacotherapyHome page
J. M Tovar and J. G Gums
Tezosentan in the Treatment of Acute Heart Failure
Ann. Pharmacother., December 1, 2003; 37(12): 1877 - 1883.
[Abstract] [Full Text] [PDF]

Home page
 J Am Coll CardiolHome page
C. M. O'Connor, W. A. Gattis, K. F. Adams Jr, V. Hasselblad, B. Chandler, A. Frey, I. Kobrin, M. Rainisio, M. R. Shah, J. Teerlink, et al.
Tezosentan in patients with acuteheart failure and acute coronary syndromes: Results of the randomized intravenous tezosentan study (ritz-4)
J. Am. Coll. Cardiol., May 7, 2003; 41(9): 1452 - 1457.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF) Free
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Article Archive
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via ISI Web of Science (21)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Torre-Amione, G.
Right arrow Articles by Pratt, C.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Torre-Amione, G.
Right arrow Articles by Pratt, C.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS