CASE REPORT

Tadalafil as treatment for idiopathic pulmonary arterial hypertension

Adriana Castro de Carvalho; André Luiz Hovnanian; Caio Julio César dos Santos Fernandes; Mônica Lapa; Carlos Jardim; Rogério Souza

Grupo de Hipertensão Pulmonar – Disciplina de Pneumologia - Instituto do Coração do Hospital das Clínicas - FMUSP - São Paulo, SP - Brazil

Mailing Address

ABSTRACT

Phosphodiesterase inhibitors like sildenafil have already been shown to improve functional capacity and hemodynamics in the treatment of pulmonary arterial hypertension. Few studies address the effects of new phosphodiesterase inhibitors as tadalafil. We report a case of a patient with idiopathic pulmonary arterial hypertension in functional class IV (New York Heart Association) with significant response to treatment with tadalafil.

Key words: Pulmonary arterial hypertension, phosphodiesterase inhibitors, sildenafil tadalafil.

Pulmonary arterial hypertension (PAH) is characterized by the proliferation and vascular remodelling that results in progressive increase of pulmonary vascular resistance with consequent right ventricular dysfunction and eventually death¹. Diagnosis for idiopathic PAH is made after exclusion of other associated factors².

The treatment for PAH has been advancing in recent years.Unfortunately, therapeutic alternatives available still faceeffectiveness limitations, which are associated to complicationsand high cost ³. The use of the phosphodiesterase-5(PDE5) inhibitor sildenafil has shown good results, withimprovement in hemodynamics and functional capacity in PAHpatients. However, many daily administrations are necessary, anddose level stands for high cost ^3-5. New PDE5inhibitors have been approved as treatment for erectiledysfunction, such as tadalafil and vardenafil. A majorcharacteristic of those agents is their half-life, but fewstudies have adressed their effectiveness and safety for PAHpatients^4-6. This paper is a report on a PAH patientwith clinical and hemodynamic improvement after treatment withtadalafil, a long lasting PDE5 inhibitor.

Case Report

A 37-year-old female patient, with progressive dyspnea onexertion for 3 years, was submitted to echocardiogram in early2003 at another service. The echocardiogram evidenced interatrialcommunication (IAC) and right ventricle systolic pressure (RVSP)estimated at 47 mmHg. At the time, the patient was submitted toheart surgery for correction of the IAC which was not identifiedintraoperatively. At the same surgical time the patient wassubmitted to a pulmonary biopsy which revealed the presence ofarteriolar plexiform lesions compatible with PAH. The patient hada history of alcohol abuse and clinical diagnosis for Child Aalcoholic hepatopathy since 1997, without portal hypertension.There was progressive worsening of dyspnea until by September,2003, when the patient presented functional class IV (New YorkHeart Association - NYHA), with RVSP estimated at 77mmHg byechocardiogram. The patient had been on espironolactone (25mg/day), digoxin (25mg/day) and omeprazol (20mg/day).

After searching on the internet for drugs to be used forpulmonary hypertension, the patient started using 10 mg ofTadalafil every 36 hours on her own. The patient came to ourservice 12 months after she had started empirical treatment. Inthat period, she reported progressive improvement of her dyspneacondition, having changed to functional class II (NYHA).

Exams were then carried out for effective investigation of pulmonary hypertension, among them: stool samples were negative for parasites; pulmonary function, rheumatogram and thyroid function: normal; abdomen ultrasound: mild hypoechogenicity of hepatic parenchyma, with no signs of portal hypertension. Thoracic CT scan showed only suggestive signs of pulmonary hypertension (Figure 1). A new echocardiogram, after one year of treatment, showed RVSP at 58 mmHg. We decided to withdraw all medication for 72 hours to carry out right heart catheterization and acute test with vasodilator, which showed no significant response to nitric oxide (NO) (Table 1).

We decided to reintroduce tadalafil, at the same dose level,with maintenance of functional class. The 6-minute walk testcarried out while on medication resulted 516 meters, startingwith 94 bpm heart rate and reaching 141 bpm by test end. Oxygensaturation, measured by pulse oximetry, was of 93% all along thetest, without oxygen supplementation.

Discussion

From the most well known pathophysiologic pathways, three areof particular relevance for being the current targets of majortherapeutic alternatives available as treatment for PAH: theprostacyclin pathway, the endothelin pathway, and the NO pathway.NO has shown to be a powerful vasodilator and inhibitor ofmuscular proliferation. NO activates guanylate cyclase, whichstimulates the production of cGMP in smooth muscle cells andpromotes their relaxation. NO levels may be reduced in PAH⁷.

Phosphodiesterases are a family of enzymes that inactivatecGMP and have different tissue distribution andaffinities⁶. PDE5 can be found in quite high volume inpulmonary vasculature. Therefore, its inhibition – which extendscGMP half-life, leading to vasodilation – has been investigatedas treatment for PAH ⁷.

Sildenafil – a PDE5 selective inhibitor – has proven to be apowerful dose-dependent vasodilator^3-5. Michelakis etal have shown that it is safe to be used for 3 months, and isassociated to the improvement of hemodynamics and functionalcapacities of PAH patients. It is probably a more affordablealternative to current treatments³. Clinical andfunctional improvement has been shown through the use ofsildenafil both for idiopathic PAH as for conditions associatedto pulmonary hypertension ⁸.

New PDE5 selective inhibitors - vardenafil and tadalafil –with the same action mechanism, although with their ownpharmacokinetic properties, have been launched as treatment forerectile dysfunction, but few studies addressed their use forPAH. Ghofrani et al have compared the hemodynamic effects ofvardenafil and tadalafil in the pulmonary and systemicvasculature of PAH patients for 120 minutes. All PDE5 inhibitorscaused significant pulmonary vasodilation, but differed in thetime for maximal effect and selectivity. Tadalafil showed maximaleffect from 75 to 90 minutes (against 40 to 45 for vardenafil and60 min for sildenafil). Tadalafil and sildenafil reported higherselectivity for pulmonary vasculature (reduction in pulmonaryvascular resistance/systemic vascular resistance), and onlysildenafil reported improvement of arterialoxygenation⁶.

Palmieri et al have described a PAH case treated with 20 mg oftadalafil every other day. Improvement of functional class (NYHA)and of RVSP in echocardiogram after 6 months of treatment wasreported. As for our patient with diagnosis for PAH,non-responsive to NO through right heart catheterization,tadalafil was started at a lower dose (10 mg) every 36 hours onher own account after information collected on lay media. Thepatient also reported improvement of clinical condition and offunctional class, with RVSP reduction – from 77 to 58 mmHg onechocardiogram. The patient has been on medication for over ayear. As improvement was evident and no adverse effects werereported, the same dose level was kept. Furthermore, the distanceof the six-minute walk test is indicative of good prognosis atlong term after treatment is established ¹⁰.

The use of new PDE5 inhibitors as tadalafil may be analternative to treat PAH, and may sponsor higher compliance totreatment since half-life is longer, with one singleadministration everyday or every other day. Furtherpharmacodynamic studies are necessary specifically for PAHpatients to find out whether the dose-response component ispresent or not, to then define the ideal dose level for suchcondition.

References

1. Rubin LJ. Primary pulmonary hypertension. Chest. 1993; 104: 236-50.        [ Links ]

2. Simonneau G, Galiè N, Rubin LJ, Langleben D, Seeger W, Domenighetti G, et al. Clinical classification of pulmonary hypertension. J Am Coll Cardiol. 2004; 43: 5S-12S.        [ Links ]

3. Michelakis ED, Tymchak W, Noga M, Webster L, Wu XC, Lien D, et al. Long-term treatment with oral sildenafil is safe and improves functional capacity and hemodynamics in patients with pulmonary arterial hypertension. Circulation. 2003; 108: 2066-9.        [ Links ]

4. Wilkens H, Guth A, Konig J, Forestier N, Cremers B, Hennen B, et al. Effect of inhaled iloprost plus oral sildenafil in patients with primary pulmonary hypertension. Circulation. 2001; 104: 1218-22.        [ Links ]

5. Michelakis ED, Tymchak W, Lien D, Webster L, Hashimoto K, Archer S. Oral sildenafil is an effective and specific pulmonary vasodilator in patients with pulmonary arterial hypertension: comparison with inhaled nitric oxide. Circulation. 2002; 105: 2398-403.        [ Links ]

6. Ghofrani HA, Voswinckel R, Reichenberger F, Olschewski H, Haredza P, Karadas B, et al. Differences in hemodynamic and oxygenation responses to three different phosphodiesterase-5 inhibitors in patients with pulmonary arterial hypertension. J Am Coll Cardiol. 2004; 44: 1488-96.        [ Links ]

7. Humbert M, Sitbon O, Simonneau G. Treatment of pulmonary arterial hypertension. N Engl Med. 2004; 351(14): 1425-36.        [ Links ]

8. Fernandes CJC, Jardim C, Carvalho LA, Farias AQ, Terra-Filho M, Souza R. Clinical response to sildenafil in pulmonary hypertension associated to Gaucher's disease. J Inherit Metab Dis. 2005; 28(4): 603-5.        [ Links ]

9. Palmieri EA, Lembo D, Affuso F, Fazio S. Tadalafil in primary pulmonary arterial hypertension. Ann Intern Med. 2004; 141(9): 743-4.        [ Links ]

10. Sitbon O, Humbert M, Nunes H, Parent F, Garcia G, Herve PG, et al. Long-term intravenous epoprostenol infusion in primary pulmonary hypertension: prognostic factors and survival. J Am Coll Cardiol. 2002; 40(4): 780-8.        [ Links ]

Mailing Address:
Rogério Souza
Rua Afonso de Freitas, 556/12
04006-052 – São Paulo, SP - Brazil
E-mail: rgrsz@uol.com.br

Manuscript received September 30, 2005; revised manuscript January 3, 2006; accepted January 3, 2006.