Correspondence

Phosphodiesterase Inhibitors for Pulmonary Hypertension

N Engl J Med 2010; 362:559-560February 11, 2010

Article

To the Editor:

In their review of the use of phosphodiesterase type 5 inhibitors for the treatment of pulmonary arterial hypertension (Nov. 5 issue),1 Archer and Michelakis report that some patients who actually have secondary pulmonary hypertension as a result of left ventricular dysfunction receive a misdiagnosis of pulmonary arterial hypertension and that their consequent exposure to vasodilatators was associated with clinical worsening early after initiation of treatment. The authors should also have mentioned that a similar observation has been reported for a specific cause of pulmonary arterial hypertension, pulmonary veno-occlusive disease.2 A careful examination of clinical and radiologic findings in patients with pulmonary arterial hypertension should be performed to identify pulmonary veno-occlusive disease, since the most accurate diagnostic procedure, open-lung biopsy, is hazardous in such patients. Indeed, in patients with hemodynamically proven pulmonary arterial hypertension, high-resolution computed tomography of the chest showing ground-glass opacities, septal lines, and mediastinal node enlargement should be considered as highly probable evidence of pulmonary veno-occlusive disease.2,3 Such patients should not receive primary treatment with oral phosphodiesterase type 5 inhibitors. Instead, those patients should be quickly considered for lung transplantation, if they are eligible, and therefore evaluated by multidisciplinary expert teams, working in a shared-care approach, before treatment with vasodilator drugs is initiated.4

Emmanuel Bergot, M.D., M.B.Sc.
Romain Magnier, M.D.
Gérard Zalcman, M.D., Ph.D.
Caen University Hospital, Caen, France
zalcman-g@chu-caen.fr

Dr. Bergot reports receiving speaking fees from Actelion Pharmaceuticals (France); and Dr. Zalcman, receiving grant support from GlaxoSmithKline, Actelion, and Pfizer. No other potential conflict of interest relevant to this letter was reported.

4 References

1
Archer SL, Michelakis ED. Phosphodiesterase type 5 inhibitors for pulmonary arterial hypertension. N Engl J Med 2009;361:1864-1871
Full Text | Web of Science | Medline

2
Montani D, Achouh L, Dorfmuller P, et al. Pulmonary veno-occlusive disease: clinical, functional, radiologic, and hemodynamic characteristics and outcome of 24 cases confirmed by histology. Medicine (Baltimore) 2008;87:220-223
CrossRef | Web of Science | Medline

3
Montani D, Price LC, Dorfmuller P, et al. Pulmonary veno-occlusive disease. Eur Respir J 2009;33:189-200
CrossRef | Web of Science | Medline

4
Humbert M, Sitbon O, Chaouat A, et al. Pulmonary arterial hypertension in France: results from a national registry. Am J Respir Crit Care Med 2006;173:1023-1030
CrossRef | Web of Science | Medline

To the Editor:

We wish to raise a number of concerns regarding the discussion by Archer and Michelakis. They provide no consensus definition of pulmonary hypertension with exercise.1,2 The term “secondary” pulmonary hypertension has been abandoned.2 A positive inotropic effect of phosphodiesterase type 5 inhibitors has not been shown in patients with pulmonary arterial hypertension and is speculative.

It is unclear why sildenafil is considered to be “slightly” more efficacious than tadalafil, absent a head-to-head comparison. In fact, only tadalafil has been shown to improve the time to clinical worsening.3 The authors recommend administration of up to 80 mg of sildenafil three times a day, but when making a cost comparison with bosentan they recommend administration of 20 mg of sildenafil three times a day (tadalafil is not included in the comparison).

The authors interpret with “caution” evidence-based guidelines and cite an old and incomplete meta-analysis.4 The authors did not cite a more recent and comprehensive meta-analysis, which included all published randomized, controlled studies of pulmonary arterial hypertension and showed a 43% reduction in mortality in an average period of 14 weeks.5

We believe that recent publications endorsed by three medical societies provide a more balanced, evidence-based guideline to physicians who care for patients with this complex condition.2

Nazzareno Galiè, M.D.
University of Bologna, Bologna, Italy
nazzareno.galie@unibo.it

Lewis J. Rubin, M.D.
University of California at San Diego, San Diego, CA

Gerald Simonneau, M.D.
University of Paris Sud, Paris, France

Dr. Galiè reports receiving lecture fees from Actelion, Bayer, GlaxoSmithKline, Eli Lilly, and Pfizer and serving on steering committees for Actelion, Bayer, GlaxoSmithKline, Eli Lilly, Pfizer, and United Therapeutics; his institution has received research grants from Actelion, GlaxoSmithKline, Eli Lilly, and Pfizer. Dr. Rubin reports serving as an investigator and consultant for Pfizer, Gilead, Actelion, and United Therapeutics and having an equity interest in United Therapeutics. Dr. Simonneau reports receiving consulting and lecture fees from Actelion, Bayer, GlaxoSmithKline, Eli Lilly, and Pfizer and research grants from Actelion, GlaxoSmithKline, Eli Lilly, Pfizer, and United Therapeutics. No other potential conflict of interest relevant to this letter was reported.

5 References

1
Badesch DB, Champion HC, Gomez-Sanchez MA, et al. Diagnosis and assessment of pulmonary arterial hypertension. J Am Coll Cardiol 2009;54:Suppl:S55-S56
CrossRef | Web of Science | Medline

2
Galie N, Hoeper M, Humbert M, et al. Guidelines on diagnosis and treatment of pulmonary hypertension: The Task Force on Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS), endorsed by the International Society of Heart and Lung Transplantation (ISHLT). Eur Heart J 2009;30:2493-2537
CrossRef | Web of Science | Medline

3
Galie N, Brundage BH, Ghofrani HA, et al. Tadalafil therapy for pulmonary arterial hypertension. Circulation 2009;119:2894-2903
CrossRef | Web of Science | Medline

4
Macchia A, Marchioli R, Marfisi R, et al. A meta-analysis of trials of pulmonary hypertension: a clinical condition looking for drugs and research methodology. Am Heart J 2007;153:1037-1047
CrossRef | Web of Science | Medline

5
Galie N, Manes A, Negro L, Palazzini M, Bacchi-Reggiani ML, Branzi A. A meta-analysis of randomized controlled trials in pulmonary arterial hypertension. Eur Heart J 2009;30:394-403
CrossRef | Web of Science | Medline

Author/Editor Response

We are afraid that Bergot and colleagues misunderstood our cautionary note regarding the use of endothelin antagonists in patients with left ventricular dysfunction. Clinical trials of these agents were terminated prematurely because of an increased risk of illness and death in such patients. We do share their concern that patients with pulmonary veno-occlusive disease may be at risk of pulmonary edema when treated with vasodilators. However, there have been reports on small series of patients in which epoprostenol was well tolerated (if not beneficial). The response of patients with pulmonary veno-occlusive disease to sildenafil is not predictable. An authoritative review from the Centre National de Référence de l'Hypertension Artérielle Pulmonaire cites several case reports and series of patients showing a favorable response to sildenafil (even as monotherapy).1 The authors mention unpublished cases of pulmonary veno-occlusive disease from their center in which pulmonary edema developed in response to sildenafil, but they include phosphodiesterase type 5 inhibitors in their algorithm for treatment of pulmonary veno-occlusive disease, emphasizing careful monitoring.

In response to Galiè and colleagues: we emphasize that our article was not intended to be a comprehensive review of pulmonary arterial hypertension. We stand by the discussion in which we compare phosphodiesterase type 5 inhibitors with other therapies. Comparisons are possible even though there are no head-to-head trials — work that is unlikely to be funded by the pharmaceutical industry. In the primary end points of the trials of sildenafil and tadalafil, the former was found to be slightly more efficacious than the latter. There is also a longer history of experience with sildenafil. Although tadalafil delayed the time to clinical worsening, the relative importance of this end point is not necessarily agreed on by all experts. Whereas in the sildenafil pivotal trial all tested doses improved the primary end point, in the tadalafil trial only the highest of the three doses tested reached significance. We discussed potential up-titration of sildenafil to 80 mg three times daily, but this step is infrequently taken. The bosentan dose cannot be up-titrated because of serious dose-dependent, hepatic toxicity. Last, a meta-analysis of short-term trials of therapy for pulmonary arterial hypertension, in which survival was not a predetermined end point, does not allow a reliable estimation of survival benefits.

Stephen Archer, M.D.
University of Chicago, Chicago, IL
sarcher@medicine.bsd.uchicago.edu

Evangelos D. Michelakis, M.D.
University of Alberta, Edmonton, AB, Canada

Since publication of their article, the authors report no further potential conflict of interest.

This letter (10.1056/NEJMc0912127) was updated on March 24, 2010, at NEJM.org.

1 References

1
Montani D, Price LC, Dorfmuller P, et al. Pulmonary veno-occlusive disease. Eur Respir J 2009;33:189-200
CrossRef | Web of Science | Medline

Citing Articles (4)

Citing Articles

1
Paolo Gresele, Stefania Momi, Emanuela Falcinelli. (2011) Anti-platelet therapy: phosphodiesterase inhibitors. British Journal of Clinical Pharmacology 72:4, 634-646
CrossRef
2
Huan Huang. 2011. Signal Transduction in Trypanosoma cruzi. , 325-344.
CrossRef
3
Wouter Jacobs, Anco Boonstra, Monika Brand, Daniel M. Rosenberg, Berthold Schaaf, Pieter E. Postmus, Anton Vonk Noordegraaf. (2010) Long-term outcomes in pulmonary arterial hypertension in the first-line epoprostenol or first-line bosentan era. The Journal of Heart and Lung Transplantation 29:10, 1150-1158
CrossRef
4
Motohiro NISHIDA, Shota SAIKI, Naoyuki KITAJIMA, Michio NAKAYA, Yoji SATO, Hitoshi KUROSE. (2010) Regulation of Cardiovascular Functions by the Phosphorylation of TRPC Channels. YAKUGAKU ZASSHI 130:11, 1427-1433
CrossRef