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Editorial |

Use of Parenteral Prostanoids: Important Insights for CHEST Physicians FREE TO VIEW

C. Gregory Elliott, MD, FCCP
Author and Funding Information

CORRESPONDENCE TO: C. Gregory Elliott, MD, FCCP, Department of Medicine, Intermountain Medical Center, 5121 S. Cottonwood, #307, Murray, UT 84107


Copyright 2016, American College of Chest Physicians. All Rights Reserved.


Chest. 2016;149(3):615-616. doi:10.1016/j.chest.2015.11.024
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In 1951, Dresdale et al described “primary pulmonary hypertension” (PPH), a progressively fatal disease for which there was no effective treatment. Then, in 1984, Higenbottam et al reported that a continuous infusion of epoprostenol dramatically improved the health of a young woman who was bedridden with PPH. Twelve years later, Barst et al showed that continuous infusion of epoprostenol produced symptomatic and hemodynamic improvement as well as improved survival for patients with severe PPH. Soon, others demonstrated the benefits of epoprostenol infusion in patients with “secondary” pulmonary hypertension; this led to a paradigm shift that allowed physicians to administer epoprostenol to patients with severe pulmonary arterial hypertension (PAH).

FOR RELATED ARTICLE SEE PAGE 660

The past 2 decades have witnessed dramatic advances in the treatment of PAH, including regulatory approval of oral, inhaled, and subcutaneous medications based on data from rigorous randomized clinical trials with important clinical end points. Experts have crafted guidelines for the treatment of PAH that integrate evidence from these clinical trials with the judgment of experienced clinicians.,, The guidelines uniformly recommend parenteral prostanoid therapy for patients with PAH who are at high risk of dying from PAH; yet investigators from the REVEAL Registry reported that many PAH-related deaths occurred without parenteral prostanoid therapy.

How can this be? In this issue of CHEST (see page 660), Hay et al provide retrospective observations of PAH treatment from 2008 to 2012 at one tertiary referral center. The authors report that 40 of 101 patients with PAH did not receive parenteral prostanoids before death. Thirty of these 40 patients either refused or were not considered candidates for parenteral prostanoids; the remaining 10 patients did not have documentation of an evaluation for parenteral prostanoid therapy. In an earlier report from another tertiary center for the care of patients with PAH, Tonelli et al prospectively investigated the deaths of 84 patients with PAH patients between 2008 and 2012. In that cohort, PAH was adjudicated as either the direct cause or a contributing cause of 74 of the 84 deaths (88%) and most of the 74 patients (70%) received parenteral prostanoid therapy. Tonelli et al reported that patients who did not receive parenteral prostanoids had valid reasons to forgo this therapy.

These two studies provide several important observations and directions for future efforts. First, both research groups reported that accurate determination of the cause of death was often difficult. Centers that treat patients with PAH need validated methods to identify deaths caused by PAH, deaths in which PAH was a contributor, and deaths unrelated to PAH. Sudden deaths are especially important because they may be expected (eg, the patient has advanced PAH and right heart failure) or unexpected (eg, the patient has PAH with markers of a good prognosis). Study of unexpected deaths provides the pulmonary hypertension community with a real opportunity to identify the cause(s) (eg, pulmonary embolism, arrhythmia, interruption of IV epoprostenol) and develop methods to prevent these untimely deaths. Such work is paramount in an era that focuses on patient safety.

Second, there are legitimate reasons to withhold parenteral prostanoids from patients who meet guidelines for treatment with a parenteral prostanoid. Hay et al reported that parenteral prostanoids were not offered to patients with significant comorbid illnesses including metastatic cancer, concomitant mild or moderate parenchymal lung disease, end-stage renal disease, severe debility, complex congenital heart disease, and hypertrophic cardiomyopathy. Since patients with PAH often have comorbidities, clinicians and patients with PAH may benefit from studies that examine the efficacy and safety of parenteral prostanoids in patients with some of these comorbidities, to better inform the decision to withhold potentially life-saving therapy. Previous inconsistent compliance with medications or follow-up was another reason for withholding parenteral prostanoids, as was the inability to manage a parenteral prostanoid. For example, Tonelli et al withheld parenteral prostanoids from a patient with dementia and from a patient with frequent catheter-related infections. Because variation in practice is common, experienced clinicians who care for patients with PAH probably withhold parenteral prostanoids differentially. Thus, another opportunity exists to examine variations in the way that clinicians use parenteral prostanoids.

Both research teams reported that some patients with PAH refused parenteral prostanoid therapy., Neither report describes the reasons why patients refused parenteral prostanoid therapy, but it is likely that these patients believed that the burden of managing the medications, infusion pumps, and side effects of prostanoids and the risks of the delivery systems were not acceptable, even with the prospect of improved function and survival. Once again, clinicians and patients with PAH may benefit from additional investigation to understand the process of refusal of potentially life-saving treatment.

Third, documentation of an evaluation for treatment with parenteral prostanoids is important for patients with PAH who are at high risk for death from PAH. Predictors of mortality for patients with PAH are well defined. They include World Health Organization functional class III or IV, low 6-min walk distance (<300 m), elevated brain natriuretic peptide, and evidence of right ventricular failure on echocardiography or at catheterization. The evaluation should include a clear description of the reason(s) why parenteral prostanoid therapy was not initiated. Ideally such evaluations should be performed by clinicians at centers that have adequate experience prescribing and managing parenteral prostanoids.

Finally, the reports authored by Hay et al and Tonelli et al originated from tertiary referral centers. Therefore, there is legitimate concern that patients with advanced PAH may die without referral to centers with the training and resources to use parenteral prostanoids. The current report does not address this important issue, but CHEST physicians should note that guideline statements uniformly recommend referral of patients with PAH to expert pulmonary hypertension centers,,; and the Pulmonary Hypertension Association has initiated a process to accredit Centers of Comprehensive Care based on their resources and practice. These centers should work collaboratively to refine the use of parenteral prostanoids so that all functional class IV patients with PAH either receive parenteral prostanoid therapy or have a well-documented description of the decision to forego this medically indicated therapy.

References

Dresdale DT .Schultz M .Michtom RJ . Primary pulmonary hypertension. I. Clinical and hemodynamic study. Am J Med. 1951;11:686-705 [PubMed]journal. [CrossRef] [PubMed]
 
Higenbottam T. .Wheeldon D. .Wells F. .Wallwork J. . Long-term treatment of primary pulmonary hypertension with continuous intravenous epoprostenol (prostacyclin). Lancet. 1984;1:1046-1047 [PubMed]journal. [PubMed]
 
Barst R.J. .Rubin L.J. .Long W.A. .et al A comparison of continuous intravenous epoprostenol (prostacyclin) with conventional therapy for primary pulmonary hypertension. The Primary Pulmonary Hypertension Study Group. N Engl J Med. 1996;334:296-302 [PubMed]journal. [CrossRef] [PubMed]
 
Badesch D.B. .Tapson V.F. .McGoon M.D. .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 [PubMed]journal. [PubMed]
 
Simonneau G. .Galie N. .Rubin L.J. .et al Clinical classification of pulmonary hypertension. J Am Coll Cardiol. 2004;43:5S-12S [PubMed]journal. [CrossRef] [PubMed]
 
Force AT, Galie N, Humbert M, et al. 2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension: the Joint Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS) endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC), International Society for Heart and Lung Transplantation (ISHLT) [published online ahead of print August 29, 2015].Eur Heart J.pii:ehv317.
 
McLaughlin V.V. .Archer S.L. .Badesch D.B. .et al ACCF/AHA 2009 expert consensus document on pulmonary hypertension: a report of the American College of Cardiology Foundation task force on expert consensus documents and the American Heart Association: Developed in collaboration with the American College of Chest Physicians, American Thoracic Society, Inc., and the Pulmonary Hypertension Association. Circulation. 2009;119:2250-2294 [PubMed]journal. [CrossRef] [PubMed]
 
Taichman D.B. .Ornelas J. .Chung L. .et al Pharmacologic therapy for pulmonary arterial hypertension in adults: CHEST guideline and expert panel report. Chest. 2014;146:449-475 [PubMed]journal. [CrossRef] [PubMed]
 
Farber H.W. .Miller D.P. .Meltzer L.A. .McGoon M.D. . Treatment of patients with pulmonary arterial hypertension at the time of death or deterioration to functional class IV: insights from the Reveal Registry. J Heart Lung Transplant. 2013;32:1114-1122 [PubMed]journal. [CrossRef] [PubMed]
 
Hay B.R. .Pugh M.E. .Robbins I.M. .Hemnes A.R. . Parenteral prostanoid use at a tertiary referral center: a retrospective cohort study. Chest. 2016;149:660-666 [PubMed]journal
 
Tonelli A.R. .Arelli V. .Minai O.A. .et al Causes and circumstances of death in pulmonary arterial hypertension. Am J Respir Crit Care Med. 2013;188:365-369 [PubMed]journal. [CrossRef] [PubMed]
 
Shekelle P.G. .Pronovost P.J. .Wachter R.M. .et al The top patient safety strategies that can be encouraged for adoption now. Ann Intern Med. 2013;158:365-368 [PubMed]journal. [CrossRef] [PubMed]
 

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References

Dresdale DT .Schultz M .Michtom RJ . Primary pulmonary hypertension. I. Clinical and hemodynamic study. Am J Med. 1951;11:686-705 [PubMed]journal. [CrossRef] [PubMed]
 
Higenbottam T. .Wheeldon D. .Wells F. .Wallwork J. . Long-term treatment of primary pulmonary hypertension with continuous intravenous epoprostenol (prostacyclin). Lancet. 1984;1:1046-1047 [PubMed]journal. [PubMed]
 
Barst R.J. .Rubin L.J. .Long W.A. .et al A comparison of continuous intravenous epoprostenol (prostacyclin) with conventional therapy for primary pulmonary hypertension. The Primary Pulmonary Hypertension Study Group. N Engl J Med. 1996;334:296-302 [PubMed]journal. [CrossRef] [PubMed]
 
Badesch D.B. .Tapson V.F. .McGoon M.D. .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 [PubMed]journal. [PubMed]
 
Simonneau G. .Galie N. .Rubin L.J. .et al Clinical classification of pulmonary hypertension. J Am Coll Cardiol. 2004;43:5S-12S [PubMed]journal. [CrossRef] [PubMed]
 
Force AT, Galie N, Humbert M, et al. 2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension: the Joint Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS) endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC), International Society for Heart and Lung Transplantation (ISHLT) [published online ahead of print August 29, 2015].Eur Heart J.pii:ehv317.
 
McLaughlin V.V. .Archer S.L. .Badesch D.B. .et al ACCF/AHA 2009 expert consensus document on pulmonary hypertension: a report of the American College of Cardiology Foundation task force on expert consensus documents and the American Heart Association: Developed in collaboration with the American College of Chest Physicians, American Thoracic Society, Inc., and the Pulmonary Hypertension Association. Circulation. 2009;119:2250-2294 [PubMed]journal. [CrossRef] [PubMed]
 
Taichman D.B. .Ornelas J. .Chung L. .et al Pharmacologic therapy for pulmonary arterial hypertension in adults: CHEST guideline and expert panel report. Chest. 2014;146:449-475 [PubMed]journal. [CrossRef] [PubMed]
 
Farber H.W. .Miller D.P. .Meltzer L.A. .McGoon M.D. . Treatment of patients with pulmonary arterial hypertension at the time of death or deterioration to functional class IV: insights from the Reveal Registry. J Heart Lung Transplant. 2013;32:1114-1122 [PubMed]journal. [CrossRef] [PubMed]
 
Hay B.R. .Pugh M.E. .Robbins I.M. .Hemnes A.R. . Parenteral prostanoid use at a tertiary referral center: a retrospective cohort study. Chest. 2016;149:660-666 [PubMed]journal
 
Tonelli A.R. .Arelli V. .Minai O.A. .et al Causes and circumstances of death in pulmonary arterial hypertension. Am J Respir Crit Care Med. 2013;188:365-369 [PubMed]journal. [CrossRef] [PubMed]
 
Shekelle P.G. .Pronovost P.J. .Wachter R.M. .et al The top patient safety strategies that can be encouraged for adoption now. Ann Intern Med. 2013;158:365-368 [PubMed]journal. [CrossRef] [PubMed]
 
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