Long-term results after addition of sildenafil in idiopathic PAH patients on bosentan.

Abstract: Idiopathic pulmonary arterial hypertension is a disease involving small muscular pulmonary arteries and arterioles. Treatment with prostacyclin analogs and endothelin receptor antagonists is the cornerstone of therapy in these patients. Recent evidence suggests that phosphodiesterase-5 inhibitors such as sildenafil may improve functional capacity and hemodynamics in patients with pulmonary arterial hypertension. Despite these advances, pulmonary arterial hypertension remains a deadly and progressive disease and it has been suggested that combination therapy aimed at multiple targets may produce a greater improvement while minimizing adverse effects. We report three patients who declined after initial improvement on bosentan and subsequently showed an improvement in their functional capacity and brain natriuretic peptide (BNP) with the addition of sildenafil. This benefit has been sustained over a mean follow-up period of 19 (range 12-24) months.

Key Words: pulmonary hypertension, bosentan, sildenafil, endo-thelin, pulmonary vascular disease

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Idiopathic pulmonary arterial hypertension (IPAH) is a vas-culopathy of the small muscular pulmonary arteries and arterioles that can be idiopathic or associated with systemic diseases. (1) Treatment with prostacyclin analogs and endothelial receptor antagonists is considered the cornerstone of therapy for patients with pulmonary arterial hypertension (PAH). (2) Despite advances in the understanding of its pathogenesis that have translated into new therapeutic modalities and improved patient outcomes, PAH is still progressive and often fatal. (3) Recent evidence suggests that compared with placebo, daily oral sildenafil significantly improved exercise capacity and hemodynamics in patients with PAH. (4) In this progressive disease with a complex pathogenesis involving multiple pathways, combination therapy has been suggested as a possible mechanism for improving functional capacity and possibly survival. (5,6) We report long-term results in three patients with IPAH on bosentan, in whom sildenafil was successfully used as rescue therapy.

Case Reports

The first patient is a 50-year-old Caucasian woman with schizophrenia, who was diagnosed with IPAH in 2001 after presenting with shortness of breath, fatigue, and pedal edema. Her initial right heart catheterization showed a mean pulmonary artery pressure (mPAP) of 57 mm Hg and a cardiac index (CI) of 1.5 L/min/[m.sup.2]. She was not felt to be a candidate for prostacyclin therapy due to concerns regarding her ability to care for herself given her schizophrenia. The patient was placed on bosentan 62.5 mg b.i.d. and later increased to 125 b.i.d. Her 6-minute walking distance (6MW), New York Heart Association (NYHA) functional class, and brain natriuretic peptide (BNP) measurements are shown in the Table. On bosentan she improved to a functional class II with a better 6MW score. Over the course of the next year she developed increasing ascites and pedal swelling with a worsening of functional capacity (to NYHA III), BNP, and 6MW, and an increase in right ventricular systolic pressure (RVSP) by echocardiography, and required multiple hospitalizations for IV diuretic therapy. The addition of sildenafil in July 2003 resulted in significant improvement in her functional parameters along with BNP and RVSP and she has not required any further hospitalizations for worsening right ventricular overload. This benefit has been maintained at approximately 22 months and she is currently in NYHA functional class II with an RVSP of 83 mm Hg, BNP 77, and 6MW of 1,395 ft.

The second patient is a 55-year-old Caucasian woman who was diagnosed to have IPAH after presenting with exertional dyspnea, hypoxemia, and a syncopal episode in 2000. Right heart catheterization showed an mPAP of 62 mm Hg and a CI of 1.7 L/min/[m.sup.2]. She responded very well to IV epoprostenol with improved functional capacity and 6MW. She was placed on bosentan 2 years later, in an effort to discontinue epoprostenol, due to recurrent line infections causing multiple hospital admissions. Epoprostenol was progressively decreased from 20 ng/kg/min to 7 ng/kg/min. At this time she was admitted and epoprostenol was progressively decreased. This resulted in worsening of her hemodynamics and the CI declined to 1.9 from 2.4 and the mixed venous oxygen saturation (MV[O.sub.2]) to 59% from 64% with mPAP stable at 52 mm Hg and a decision was made by the clinician to continue her epoprostenol. Four months later, after another episode of line infection, she was readmitted to the medical ICU and after a 25 mg dose of sildenafil, epoprostenol taper was performed. Over the next 24 hours, epoprostenol was tapered off as sildenafil was titrated up to 100 mg t.i.d. The addition of sildenafil to bosentan resulted in improvement in her 6MW and BNP over the next 6 months (Table). This benefit has persisted over the last 24 months and she continues to be NYHA I with an RVSP of 93 mm Hg, BNP of 128, and 6MW of 1,600 ft.

The third patient is a 63-year-old Caucasian woman who was diagnosed with IPAH when she was noted to have unexplained hypoxemia after elective knee replacement surgery in 2001. Pulmonary angiography done to rule out pulmonary embolism showed no emboli but did reveal elevated pulmonary arterial pressures with an mPAP of 72 mm Hg. She did very well on epoprostenol over the next 2 years; however, she had multiple episodes of venous catheter site infection as well as catheter-related bacteremia requiring hospitalization. The patient was transitioned to subcutaneous treprostinil sodium and bosentan 125 b.i.d. She subsequently noticed a decline in her functional capacity (Table), increased pedal edema with a rising BNP and developed a debilitating rash over her body which was felt to be due to treprostinil sodium. She was admitted to the medical ICU where treprostinil sodium was tapered off and right heart catheterization showed a Cl of 1.8 L/min/[m.sup.2] and an MV[O.sub.2] of 42%, despite being on bosentan. Sildenafil was instituted at a dose of 25 mg t.i.d., titrating up to 75 mg t.i.d. and her CI improved to 2.4 L/min/[m.sup.2] with an MV[O.sub.2] of 68%. She subsequently noted an improvement in her 6MW, NYHA class, and BNP and the benefit has been maintained at approximately 12 months, where she was in NYHA class III with an RVSP of 80 mm Hg, BNP of 104, and 6MW of 740 ft. The rash on her body resolved gradually.

Discussion

To our knowledge, this is the first report of the potential long-term benefits of combination therapy with bosentan and sildenafil in patients with PAH. In the first patient, sildenafil was added as rescue therapy for worsening symptoms despite bosentan therapy, and in the other two patients, sildenafil was used as rescue therapy to allow successful discontinuation of IV epoprostenol or subcutaneous treprostinil sodium. The first patient, who was NYHA III before the addition of sildenafil, improved to NYHA II. The second patient was NYHA II on a combination of epoprostenol and bosentan but was unable to discontinue IV epoprostenol therapy. After the addition of sildenafil, she improved to NYHA I and continues to exercise and swim with no significant functional limitation. These benefits have been maintained approximately 2 years after the initiation of combination therapy. The third patient also improved by one NYHA functional class (IV to III) after the addition of sildenafil and continues to improve off treprostinol sodium. Our observation demonstrates that in selected patients, the addition of sildenafil may serve as long-term rescue therapy for patients deteriorating on bosentan alone. All three patients tolerated the combination very well with no ill effects.

Endothelial dysfunction also plays a central role in the pathophysiology of PAH and evidence suggests various abnormalities in the expression and activity of endothelin-1 in these patients. (7-9) Recent evidence suggests that long-term treatment with bosentan as first-line therapy is associated with sustained improvement in pulmonary hemodynamics and functional capacity (10,11) in patients with PAH. Vascular smooth muscle contraction and hypertrophy is central to the increased pulmonary vascular resistance characteristic of the PAH state. As part of the attempts to vasodilate the affected pulmonary vascular bed, inhibition of the phosphodiesterase-5 (PDE5) enzyme has been receiving increased attention in the medical literature in view of the known role of PDE5 in the intracellular regulation of cyclic guanosine-monophosphate (cGMP) levels. Numerous uncontrolled studies have hinted at the short- and long-term efficacy of sildenafil in patients with PAH. (12-14) Preliminary results of a multicenter, double blind, placebo-controlled study comparing 3 doses (20 mg, 40 mg, or 80 mg t.i.d.) of sildenafil to placebo were recently reported. (4) The study demonstrated that, compared with placebo, daily oral sildenafil significantly improved exercise capacity (45-50 meter treatment effect across all 3 doses in 6-min walk distance, P < 0.001), mean pulmonary artery pressure, pulmonary vascular resistance, cardiac output, and mixed venous oxygen saturation in patients with pulmonary arterial hypertension.

Sildenafil also exerts a marked synergistic effect when administered following an inhaled dose of iloprost. (12) and has been shown to improve six-minute walk distance in patients with severe PAH who were deteriorating despite ongoing iloprost therapy. (15) Sildenafil is currently being studied in combination with IV epoprostenol. We believe that since bosentan and sildenafil have differing mechanisms of action, their combination may work synergistically in patients with PAH in improving functional capacity, quality of life, and hemodynamics while minimizing side effects. A case series of nine patients with severe and progressive IPAH (16) provided preliminary evidence that the combination of bosentan and sildenafil may be a safe and effective combination over a median follow-up period of nine months. In this case series, the authors described a group of patients who demonstrated a decline after initial improvement with bosentan. In these patients, the addition of sildenafil produced stabilization or improvement in functional capacity. Coincidentally, our patients also demonstrated a significant improvement with the initial addition of bosentan but this benefit was not sustained. It should also be mentioned that all three patients described in this report started their treatment before the FDA approval of sildenafil (at a dose of 20 mg t.i.d.) and were treated at sildenafil doses ranging between 50 mg t.i.d. and 100 mg t.i.d., which are significantly higher than the FDA-approved dose.

In spite of these preliminary reports, it remains unclear whether combination therapy is truly superior to monotherapy, (16) what criteria to use when deciding who should be placed on combination therapy and at what time, and whether one combination therapy is superior to others. In light of the unresolved issues outlined above and the paucity of objective evidence, we would recommend that such combinations only be attempted by experts in the field who have substantial experience in dealing with PAH patients and have access to the resources of a pulmonary hypertension center of excellence. (17) Given the small number of patients, satisfactory answers to these and any other questions can only come through well-designed, prospective, multicenter trials. In view of the close cooperation between pulmonary hypertension centers both in North America and Europe, and a long history of successfully conducted trials, this remains a realistic and feasible approach.

References

1. McGoon M, Gutterman D, Steen V, et al. Screening, early detection, and diagnosis of pulmonary arterial hypertension: ACCP evidence-based clinical practical guidelines. Chest 2004; 126:14S-34S.

2. Channick RN, Sitbon O, Barst RJ, et al. Endothelin receptor antagonists in pulmonary arterial hypertension. J Am Coll Cardiol 2004;43:62S-67S.

3. McLaughlin VV, Shillington A, Rich S. Survival in primary pulmonary hypertension: the impact of epoprostenol therapy. Circulation 2002; 106:1477-1482.

4. Galie N, Ghofrani HA, Torbicki A, et al. Sildenafil citrate therapy for pulmonary arterial hypertension. N Engl J Med 2005;353:2148-2157.

5. Rubin LJ, Galie N. Pulmonary arterial hypertension: a look to the future. J Am Coll Cardiol 2004;43(12 Suppl S):89S-90S.

6. Galie N, Seeger W, Naeije R, et al. Comparative analysis of clinical trials and evidence-based treatment algorithm in pulmonary arterial hypertension. J Am Coll Cardiol 2004;43:81S-88S.

7. Stewart DJ, Levy RD, Cernacek P, Langleben D. Increased plasma endothelin-1 in pulmonary hypertension: marker or mediator of disease. Ann Intern Med 1999; 114:464-469.

8. 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.

9. Rubin LJ, Badesch DB, Barst RJ, et al. Bosentan therapy for pulmonary arterial hypertension. N Engl J Med 2002;346:896-903.

10. Sitbon O, Badesch DB, Channick RN, et al. Effects of the dual endo-thelin antagonist bosentan in patients with pulmonary arterial hypertension: a 1-year follow-up study. Chest 2003;124:247-254.

11. McLaughlin VV, Sitbon O, Badesch DB, et al. Survival with first-line bosentan in patients with primary pulmonary hypertension. Eur Respir J 2005;25:244-249.

12. 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.

13. 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.

14. Ghofrani HA, Wiedemann R, Rose F, et al. Sildenafil for treatment of lung fibrosis and pulmonary hypertension: a randomised controlled trial. Lancet 2002;360:895-900.

15. Ghofrani HA, Rose F, Schermuly RT, et al. Oral sildenafil as long-term adjunct therapy to inhaled iloprost in severe pulmonary arterial hypertension. J Am Coll Cardiol 2003;42:158-164.

16. Hoeper MM, Faulenbach C, Golpon H, et al. Combination therapy with bosentan and sildenafil in idiopathic pulmonary arterial hypertension. Eur Respir J 2004;24:1007-1010.

17. Mughal MM, Mandell B, James K, et al. Implementing a shared care approach to improve the management of patients with pulmonary arterial hypertension. Cleve Clin J Med 2003;70(Suppl 1):S28-S33.

I think of a hero as someone who understands the degree of
responsibility that comes with his freedom.
--Bob Dylan

Omar A. Minai, MD, FCCP, and Alejandro C. Arroliga, MD, FCCP

From the Department of Pulmonary, Allergy, and Critical Care Medicine, Cleveland Clinic Foundation, Cleveland, OH.

Reprint requests to Omar A. Minai, MD, FCCP, Staff Physician, Department of Pulmonary, Allergy, and Critical Care Medicine, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195. Email: [e-mail]

Accepted February 15, 2006.

RELATED ARTICLE: Key Points

* Patients with pulmonary arterial hypertension declining on monotherapy may obtain benefit from the addition of a second agent.

* Combination therapy can produce sustained clinical improvement in patients with pulmonary hypertension.

Table. Characteristics during follow up in patients with idiopathic PAH
on combination bosentan and sildenafil

     Baseline 1 before  3-6 months after        6-12 months after
     bosentan           bosentan                bosentan
     NYHA/              NYHA/                   NYHA/
No.  RVSP    6MW        RVSP    6MW        BNP  RVSP    6MW        BNP

1    III/88  895 RA     II/86   1325 RA    NA   II/118  1425 RA    768
2    III/NA  1340 RA    II/69   1740 RA    145  (b)     (b)        (b)
3    III/61  845 2      III/48  795 3      121  III/70  820 4      157
               lit (a)            lit (a)                 lit (a)

                                                       12-18 months
     Baseline 2 before         3-6 months after        after
     sildenafil                sildenafil              sildenafil
     NYHA/                     NYHA/                   NYHA/
No.  RVSP     6MW        BNP   RVSP    6MW        BNP  RVSP    6MW

1    III/120  1160 RA    1740  III/76  1275 RA    171  II/83   1395 RA
2    II/72    1468 RA    219   II/93   1600 RA    128  I/NA    PR
3    IV/71    DNW 5      216   III/82  645 4      92   III/80  740 4
                lit (a)                  lit (a)                 lit (a)

     12-18 months
     after
     sildenafil
No.  BNP

1    77
2    312
3    104

BNP, brain natriuretic peptide; DNW, did not walk; NA, not available;
NYHA, New York Heart Association classification; RA, room air; RVSP,
right ventricular systolic pressure by echo; 6MW, distance (in feet)
walked in six minutes; PR, patient refused.
(a) Liters of oxygen during six-minute walk test.
(b) Data for 6-12 months follow up was the most recent prior to
initiation of sildenafil (i.e. data shown for baseline).