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(Chest. 2003;124:1612-1615.)
© 2003 American College of Chest Physicians

Successful Withdrawal of Long-term Epoprostenol Therapy for Pulmonary Arterial Hypertension*

Nick H. Kim, MD; Richard N. Channick, MD and Lewis J. Rubin, MD, FCCP

* From the Pulmonary Vascular Center, University of California, San Diego, CA.

Correspondence to: Lewis J. Rubin, MD, FCCP, University of California, San Diego, 9300 Campus Point Dr, La Jolla, CA 92037; e-mail: ljrubin{at}ucsd.edu


   Abstract
TOP
 Abstract
Introduction
 Case Reports
 Discussion
 References
 
Background: IV epoprostenol treatment of pulmonary arterial hypertension (PAH) has been believed to require an indefinite duration of therapy

Objective: To describe the successful discontinuation of long-term epoprostenol therapy in four patients

Design: Case reports

Setting: Outpatient clinic, tertiary-care hospital

Patients: Four patients with acutely nonvasoreactive, World Health Organization (WHO) functional class IV PAH received long-term epoprostenol therapy. All patients subsequently demonstrated normalization of pulmonary arterial pressures on epoprostenol treatment. These patients were selected for epoprostenol withdrawal

Intervention: Down-titration and discontinuation of epoprostenol

Results: All four patients were safely transitioned from epoprostenol to oral therapies and have maintained WHO functional class I-II for a mean of 11 months (range, 8 to 16 months). The duration of epoprostenol therapy prior to discontinuation averaged 5.7 years (range, 2.4 to 13.5 years)

Conclusion: Epoprostenol may sufficiently reverse the pathogenic process in select patients with PAH to allow a transition to less complex and less invasive treatment modalities.

Key Words: epoprostenol • Flolan • pulmonary hypertension


   Introduction
TOP
 Abstract
 Introduction
Case Reports
 Discussion
 References
 
The past decade has witnessed major advances in treating pulmonary arterial hypertension (PAH) and elucidating its pathogenesis. Once considered progressive or fatal, PAH is now treatable in many patients. A major reason for this advance has been the use of epoprostenol, a drug that improves functional status, delays or obviates the need for lung transplantation, and prolongs survival in patients with PAH.1 2 3 4 However, epoprostenol therapy requires central IV access and a continuous infusion delivery system, and is best managed in specialized centers with experienced staff capable of handling its complexity and challenges. Furthermore, epoprostenol therapy is associated with significant cost and morbidity.5 6 7

Initiating epoprostenol has generally been assumed to mean life-long dependence on this treatment. We report four patients with PAH who normalized their pulmonary hemodynamics with long-term epoprostenol therapy and were transitioned to oral therapies, with long-term epoprostenol discontinued safely.


   Case Reports
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 Abstract
 Introduction
 Case Reports
Discussion
 References
 
Patient 1 is a 65-year-old woman who received a diagnosis of primary pulmonary hypertension (PPH) in 1997 after presenting with exertional dyspnea, near-syncope, and hoarseness (Ortner’s sign). Her initial and follow-up hemodynamics are shown in Table 1 . She demonstrated no acute vasoreactivity8 to epoprostenol (maximum tested dose, 6 ng/kg/min) prior to starting long-term therapy. With normalization of pulmonary arterial pressure (Ppa) at catheterization in 1999, the epoprostenol dose was reduced to alleviate potential treatment side effects of fatigue, generalized aches, and resting tachycardia. Cardiac catheterization was repeated in July 2001 with further down-titration of epoprostenol. Mean Ppa decreased from 33 to 19 mm Hg with inhaled nitric oxide (iNO) [Table 1 ]. She was discharged receiving nifedipine, 60 mg qd, and a lower dose of epoprostenol. One month later, the epoprostenol infusion was reduced until discontinued (Table 1) . Following epoprostenol discontinuation and central line removal, she was discharged receiving nifedipine, 120 mg qd, and has remained stable with World Health Organization (WHO) I-II functional status (16 months of follow-up).


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  		Table 1.. Patient 1 Initial and Follow-up Hemodynamics and Functional Class

 
Patient 2 is a 42-year-old woman who received a diagnosis of PPH in 1990, with a mean Ppa of 70 mm Hg. A single-lung transplant in 1992 was followed by allograft failure, with absent flow demonstrated on a perfusion study. She experienced progressive clinical decline and presented in 1998 with severe dyspnea on exertion and near-syncope. Mean Ppa was 80 mm Hg. Epoprostenol was initiated with improvement in symptoms, allowing her to resume work within 2 months. During cardiac catheterization in March 2001, she demonstrated vasoreactivity to iNO with a decrease in Ppa from 65/24 mm Hg (mean, 41 mm Hg; on epoprostenol, 45 ng/kg/min) to 39/15 mm Hg (mean, 25 mm Hg). Extended-release diltiazem, 120 mg/d, was added to epoprostenol. When she continued to demonstrate substantial vasoreactivity (with iNO, Ppa reduced by > 20% with increase in cardiac output) 6 months later despite increases in diltiazem to 360 mg/d, sildenafil at 25 mg tid was added followed later by bosentan (62.5 mg bid for the first month followed by 125 mg bid), with further dose reductions of epoprostenol. In February 2002, epoprostenol was weaned off (Table 2 ). She was discharged receiving bosentan, 125 mg bid; diltiazem, 240 mg bid; and sildenafil, 25 mg tid. At follow-up 10 months later, she was in WHO I functional status with a 6-min walk distance of 379 m (391 m while receiving epoprostenol).


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  		Table 2.. Hemodynamics Before and After Epoprostenol Discontinuation

 
Patient 3 is a 39-year-old woman who received a diagnosis of PPH after presenting with syncope and exertional dyspnea in 1988, with a mean Ppa of 50 mm Hg. Epoprostenol was initiated with substantial improvement in her symptoms. By 1994, she was receiving epoprostenol at 86 ng/kg/min, and had significant reduction in Ppa to 34/16 mm Hg (mean, 24 mm Hg). In January 2001, while receiving epoprostenol at 115 ng/kg/min with WHO functional class I-II, she had a 6-min walk distance of 457 m. Following several catheter-related infections, bosentan was added to her regimen in late 2001 with the intent of facilitating a transition off epoprostenol using a newly approved oral therapy. Cardiac catheterization 2 months later revealed Ppa of 24/7 mm Hg with treatment with epoprostenol at 95 ng/kg/min and bosentan at 125 mg bid. Down-titration of epoprostenol was performed with minimal change in Ppa (Table 2) . Following removal of her central line, she was discharged receiving bosentan and nifedipine twice daily (120 mg total). At 5-month follow-up, her 6-min walk distance was 417 m. She has remained in stable condition with WHO II functional status 10 months following epoprostenol discontinuation.

Patient 4 is a 54-year-old woman with limited scleroderma diagnosed with PAH after presenting with progressive dyspnea on exertion and near-syncope in 1999. Cardiac catheterization demonstrated Ppa of 76/29 mm Hg (mean, 47 mm Hg) and pulmonary vascular resistance of 8.0 Wood units. Acute testing with epoprostenol did not demonstrate vasoreactivity (maximum tested dose, 10 ng/kg/min) and long-term epoprostenol therapy was initiated. Subsequent echocardiograms during 2001, with epoprostenol therapy at 13 to 14 ng/kg/min, estimated systolic Ppa at 40 mm Hg. Her 6-min walk distance in August 2001 was 320 m. Cardiac catheterization in November 2001 revealed Ppa of 32/11 mm Hg (mean, 21 mm Hg) while receiving epoprostenol at 13 ng/kg/min. Bosentan was added with the goal of weaning epoprostenol. In April 2002, epoprostenol was titrated off (Table 2) . At 2-month follow-up after epoprostenol withdrawal, her 6-min walk distance had improved to 417 m. At 8 months, she remained in stable condition, swimming and exercising with WHO I functional status.


   Discussion
TOP
 Abstract
 Introduction
 Case Reports
 Discussion
References
 
We have demonstrated successful discontinuation of long-term epoprostenol therapy in four carefully selected patients with initially severe and nonvasoreactive PAH. All had achieved marked clinical response (baseline WHO class IV improving to I-II) and normalization of pulmonary pressures with long-term epoprostenol therapy prior to attempts at withdrawal. The average duration of epoprostenol therapy prior to discontinuation was 5.7 years (range, 2.4 to 13.5 years). These patients have maintained WHO functional class I-II for durations ranging from 8 to 16 months (mean, 11 months) after epoprostenol withdrawal. Our observations demonstrate that epoprostenol therapy may produce sufficient improvement in some patients to allow a transition to less invasive treatments.

Although epoprostenol is a pulmonary vasodilator, the majority of patients with PAH are not responsive to acute vasodilator challenge with short-acting agents such as epoprostenol, adenosine, or nitric oxide (NO).8 Despite the absence of an acute response, long-term administration of epoprostenol lowers Ppa while improving cardiac output in patients with PAH.9 The possible mechanisms responsible for this improvement include improved cardiac output, inhibition of platelet aggregation, and pulmonary vascular remodeling.10

The ability to wean off epoprostenol in our patients, all of whom had severe, nonvasoreactive PAH at time of initiation of therapy, supports the concept of a beneficial remodeling effect. Interestingly, two of our patients who were previously nonvasoreactive demonstrated acute vasodilator responsiveness after years of epoprostenol therapy; the addition of oral vasodilators facilitated the discontinuation of epoprostenol.

Several mechanisms by which epoprostenol might produce a remodeling effect have been suggested. Clapp et al11 demonstrated that prostacyclin analogs inhibit proliferation of human pulmonary artery myocytes. Long-term epoprostenol therapy in patients with PAH improves endothelial function and enhances clearance of endothelin-1 (ET-1).10 12 Endothelial dysfunction and excess production of ET-1, a potent vasoconstrictor and mitogen, have been implicated in the pathogenesis of PAH,13 and plasma levels of ET-1 correlate with disease severity.14

Bosentan, an ET-1 receptor antagonist that is the first oral treatment approved for use in PAH, was added to the regimen of three patients prior to epoprostenol discontinuation. By blocking the receptors for ET-1, bosentan may also have contributed an additional pulmonary vascular remodeling effect.13 15 Thus, any residual arteriopathy in these patients might be stabilized or further reversed, preventing the need for reintroduction of epoprostenol. Studies are currently assessing the effects of bosentan in early stages PAH and as combination therapy with prostanoids.

Sildenafil, a phosphodiesterase-5 inhibitor and pulmonary vasodilator,16 17 was initiated in one patient who demonstrated vasoreactivity after long-term epoprostenol therapy. Inhibiting phosphodiesterase-5 increases intracellular cyclic guanosine monophosphate, the messenger responsible for NO-induced vasodilation, thereby enhancing and prolonging the effects of endogenous NO. In this patient with persistent vasoreactivity to iNO despite increases in calcium-channel blocker, sildenafil was added to potentiate the vasodilator effect.

The availability of newer, less invasive, and less cumbersome treatments for PAH makes replacement of epoprostenol tempting for both patient and physician. We strongly emphasize that we selected these patients for transition to oral therapies because they had normal hemodynamics, together with marked functional improvement, prior to initiation of epoprostenol withdrawal. To date, these are the only patients in our PAH population who have met these hemodynamic and clinical criteria. Whether patients with residual pulmonary hypertension despite epoprostenol therapy can be safely transitioned to alternate therapies remains unknown, but we urge caution. Furthermore, a longer period of follow-up of these patients is needed to determine if relapse of PAH will develop that may necessitate reintroduction of prostanoid therapy.

In conclusion, long-term epoprostenol therapy may be safely weaned off and replaced with oral therapies in carefully selected patients with PAH. Epoprostenol may sufficiently reverse the pathogenic process to allow a transition to less complex and less invasive treatment modalities; however, until more experience and longer follow-up are obtained, we suggest that consideration of withdrawing epoprostenol should be reserved to individuals and centers with substantial PAH experience.


   Footnotes
 
Drs. Kim, Channick, and Rubin have been as consultants for Actelion Pharmaceuticals, and Drs. Channick and Rubin have been consultants for Pfizer Pharmaceuticals.

Abbreviations: ET-1 = endothelin-1; iNO = inhaled nitric oxide; NO = nitric oxide; PAH = pulmonary arterial hypertension; Ppa = pulmonary arterial pressure; PPH = primary pulmonary hypertension; WHO = World Health Organization

Received for publication January 17, 2003. Accepted for publication April 9, 2003.


   References
TOP
 Abstract
 Introduction
 Case Reports
 Discussion
 References
 

  1. Barst, RJ, Rubin, LJ, Long, WA, et al (1996) A comparison of continuous intravenous epoprostenol (prostacyclin) with conventional therapy for primary pulmonary hypertension: The Primary Pulmonary Hypertension Study Group. N Engl J Med 334,296-302[Abstract/Free Full Text]
  2. Badesch, DB, Tapson, VF, McGoon, MD, et al Continuous intravenous epoprostenol for pulmonary hypertension due to the scleroderma spectrum of disease: a randomized, controlled trial. Ann Intern Med 2000;132,425-434[Abstract/Free Full Text]
  3. McLaughlin, VV, Shillington, A, Rich, S Survival in primary pulmonary hypertension: the impact of epoprostenol therapy. Circulation 2002;106,1477-1482[Abstract/Free Full Text]
  4. Sitbon, O, Humbert, M, Nunes, H, et al Long-term intravenous epoprostenol infusion in primary pulmonary hypertension: prognostic factors and survival. J Am Coll Cardiol 2002;40,780-788[Abstract/Free Full Text]
  5. Rubin, LJ Primary pulmonary hypertension. N Engl J Med 1997;336,111-117[Free Full Text]
  6. Gaine, S Pulmonary hypertension. JAMA 2000;284,3160-3168[Abstract/Free Full Text]
  7. Falk, A, Lookstein, RA, Mitty, HA Flolan infusion interruption: a lethal complication during venous access. J Vasc Interv Radiol 2001;12,667-668[ISI][Medline]
  8. Rich S, ed. Executive summary of the World Symposium on Primary Pulmonary Hypertension 1998. Available at: http://www.who.int/ncd/cvd/pph.html. Accessed on October 9, 2001
  9. McLaughlin, VV, Genthner, DE, Panella, MM, et al Reduction in pulmonary vascular resistance with long-term epoprostenol (prostacyclin) therapy in primary pulmonary hypertension. N Engl J Med 1998;338,273-277[Abstract/Free Full Text]
  10. Sakamaki, F, Kyotani, S, Nagaya, N, et al Increased plasma P-selectin and decreased thrombomodulin in pulmonary arterial hypertension were improved by continuous prostacyclin therapy. Circulation 2000;102,2720-2725[Abstract/Free Full Text]
  11. Clapp, LH, Finney, P, Turcato, S, et al Differential effects of stable prostacyclin analogs on smooth muscle proliferation and cyclic AMP generation in human pulmonary artery. Am J Respir Cell Mol Biol 2002;26,194-201[Abstract/Free Full Text]
  12. Langleben, D, Barst, RJ, Badesch, D, et al Continuous infusion of epoprostenol improves the net balance between pulmonary endothelin-1 clearance and release in primary pulmonary hypertension. Circulation 1999;99,3266-3271[Abstract/Free Full Text]
  13. Giaid, A, Yanagisawa, M, Langleben, D, et al Expression of endothelin-1 in the lungs of patients with pulmonary hypertension. N Engl J Med 1993;328,1732-1739[Abstract/Free Full Text]
  14. Rubens, C, Ewert, R, Halank, M, et al Big endothelin-1 and endothelin-1 plasma levels are correlated with the severity of primary pulmonary hypertension. Chest 2001;120,1562-1569[Abstract/Free Full Text]
  15. Rubin, LJ, Badesch, DB, Barst, RJ, et al Bosentan therapy for pulmonary arterial hypertension. N Engl J Med 2002;346,896-903[Abstract/Free Full Text]
  16. Michelakis, E, Tymchak, W, Lien, D, et al Oral sildenafil is an effective and specific pulmonary vasodilator in patients with pulmonary arterial hypertension: comparison with inhaled nitric oxide. Circulation 2002;105,2398-2403[Abstract/Free Full Text]
  17. Ghofrani, HA, Wiedemann, R, Rose, F, et al Combination therapy with oral sildenafil and inhaled iloprost for severe pulmonary hypertension. Ann Intern Med 2002;136,515-522[Abstract/Free Full Text]



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