Pharmacologic Therapy for Pulmonary Arterial Hypertension in Adults: CHEST Guideline and Expert Panel Report

doi:10.1378/chest.14-0793

Chest

Volume 146, Issue 2, August 2014, Pages 449-475

https://doi.org/10.1378/chest.14-0793 Get rights and content

OBJECTIVE

Choices of pharmacologic therapies for pulmonary arterial hypertension (PAH) are ideally guided by high-level evidence. The objective of this guideline is to provide clinicians advice regarding pharmacologic therapy for adult patients with PAH as informed by available evidence.

METHODS

This guideline was based on systematic reviews of English language evidence published between 1990 and November 2013, identified using the MEDLINE and Cochrane Library databases. The strength of available evidence was graded using the Grades of Recommendations, Assessment, Development, and Evaluation methodology. Guideline recommendations, or consensus statements when available evidence was insufficient to support recommendations, were developed using a modified Delphi technique to achieve consensus.

RESULTS

Available evidence is limited in its ability to support high-level recommendations. Therefore, we drafted consensus statements to address many clinical questions regarding pharmacotherapy for patients with PAH. A total of 79 recommendations or consensus statements were adopted and graded.

CONCLUSIONS

Clinical decisions regarding pharmacotherapy for PAH should be guided by high-level recommendations when sufficient evidence is available. Absent higher level evidence, consensus statements based upon available information must be used. Further studies are needed to address the gaps in available knowledge regarding optimal pharmacotherapy for PAH.

Section snippets

Summary of Recommendations

Pharmacologic Therapy for Pulmonary Arterial Hypertension in Adults

1. We suggest that the severity of a pulmonary arterial hypertension (PAH) patient's disease be evaluated in a systematic and consistent manner, using a combination of World Health Organization (WHO) functional class (FC), exercise capacity, echocardiographic, laboratory and hemodynamic variables in order to inform therapeutic decisions (Grade CB).

2. We suggest that, whenever possible, all PAH patients be evaluated promptly at a center with expertise in the diagnosis of PAH, ideally prior to

Vasoreactivity Testing and Use of Calcium Channel Blockers

7. We suggest that patients with PAH, in the absence of contraindications, should undergo acute vasoreactivity testing using a short-acting agent at a center with experience in the performance and interpretation of vasoreactivity testing (Grade CB).

Remark: Contraindications to acute vasoreactivity testing include a low systemic blood pressure, low cardiac output or the presence of FC IV symptoms. Acute vasoreactivity testing may be complicated by hypotension, and the misinterpretation of

PAH-Specific Pharmacotherapies

Pregnancy

75. In patients with PAH, we suggest that pregnancy be avoided (Grade CB).

Remark: Estrogen-containing contraceptives may increase the risk of VTE and are not recommended for women with childbearing potential who have PAH. Additionally, the ETRA bosentan may decrease the efficacy of hormonal contraception. Bosentan, ambrisentan, macitentan and riociguat are contraindicated in pregnancy (category X; evidence of serious fetal abnormalities) and dual mechanical barrier contraceptive techniques are

Methods

The goal of this CHEST guideline project was to produce clinically relevant and useful recommendations on medical therapies for PAH for clinicians who treat adult patients with PAH. Health-care providers should use these guidelines to assist patients with treatment choices that optimize benefits and minimize harms and burdens.

In 2011, the Institute of Medicine (IOM) released new guideline standards⁶ that required significantly more scientific rigor and high-quality evidence to be considered

Pharmacologic Therapy for PAH in Adults

Lacking head-to-head comparisons of pharmacologic agents for the treatment of PAH, and because of their differing burdens and risks to patients, we recommend that drug therapy be chosen on the basis of a methodical evaluation of disease severity and the risk for further short-term deterioration. The optimal method of evaluation has not been studied. Despite variability in clinicians' approaches,⁷ the WHO FC (Table 2)¹⁸ provides a patient-centered means of assessing disease impact on a patient's

Treatment Naive PAH Patients Without Symptoms (WHO FC I) and Patients at Increased Risk for the Development of PAH

Asymptomatic (ie, those with WHO FC I) patients with PAH are rarely identified. Such patients might be identified if screening (ie, the testing of individuals without symptoms) for PH is performed. We lack evidence regarding whether the initiation of PAH-specific treatment is beneficial in patients with WHO FC I symptoms, and no therapy is approved for such use. We believe a careful history is paramount to ensure a true lack of symptoms, as opposed to a patient who has altered his or her

Vasoreactivity Testing and Use of CCBs

CCBs are a recommended treatment of pulmonary arterial hypertension (PAH) in a defined subset of patients who have a specific biomarker that predicts the response to therapy. Patients likely to respond to CCBs can be identified by hemodynamic testing with short-acting vasodilators at the time of initial evaluation.¹⁹ No other clinical characteristic or baseline hemodynamic feature predicts those patients who will respond.

Recommendation

7. We suggest that patients with PAH, in the absence of

Bosentan

Four double-blind placebo-controlled studies of bosentan for the treatment of PAH overall found that bosentan resulted in improvements in exercise capacity, hemodynamics, and time to clinical worsening, with a significantly decreased hazard for hospitalization compared with placebo. The first study enrolled 32 patients with WHO FC III or IV disease due to IPAH or PAH associated with systemic sclerosis.²⁹ After 12 weeks of treatment, the mean placebo-corrected improvement in 6MWD was 76 m (95%

Pregnancy

Pregnancy was addressed in the 2004 ACCP Medical Therapy Guidelines document.⁶⁹ Following is an update to that section of the document. Many patients with PAH are women of childbearing age. The hemodynamic demands of pregnancy are substantial and include an increase of 30% to 50% in blood volume, a similar increase in CO, a 10- to 20-beat/min increase in heart rate, an increase in stroke volume, and decreases in both systemic vascular resistance and BP.69, 70 These hemodynamic changes begin

Conclusions

The options for pharmacotherapy in patients with PAH include several drug classes and delivery routes. The choice of therapy should be made by experienced clinicians and must be based upon an appropriately established diagnosis and evaluation of the patient's disease severity. Available evidence is sufficient to inform a limited number of strong guideline recommendation statements regarding the effect of a specific therapy or combination of therapies on select outcomes in distinct groups of

Acknowledgments

Author contributions: D. T. was the chairperson of the panel. R. Y. was the GOC liaison. D. T., J. O., L. C., J. R. K., S. L., J. M., H. P., S. R., N. S., E. B. R., T. T., R. Y., C. G. E., and D. B. served as panelists and were on the writing committee for these guidelines.

Financial/nonfinancial disclosures: The authors have reported to CHEST the following conflicts of interest: Until 2009, Dr Taichman was an employee of the University of Pennsylvania, which received research grant support from

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Drs Elliott and Badesch contributed equally to this manuscript.

FUNDING/SUPPORT: This study was funded in total by internal funds from the American College of Chest Physicians.

DISCLAIMER: CHEST Guidelines are intended for general information only, are not medical advice, and do not replace professional medical care and physician advice, which always should be sought for any medical condition. The complete disclaimer for this guideline can be accessed at http://www.chestnet.org/Guidelines-and-Resources/Guidelines-and-Consensus-Statements/Methodology.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details.

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Evidence-Based MedicineFeaturedPharmacologic Therapy for Pulmonary Arterial Hypertension in Adults: CHEST Guideline and Expert Panel Report

OBJECTIVE

METHODS

RESULTS

CONCLUSIONS

Section snippets

Summary of Recommendations

Pharmacologic Therapy for Pulmonary Arterial Hypertension in Adults

Vasoreactivity Testing and Use of Calcium Channel Blockers

PAH-Specific Pharmacotherapies

Pregnancy

Methods

Pharmacologic Therapy for PAH in Adults

Treatment Naive PAH Patients Without Symptoms (WHO FC I) and Patients at Increased Risk for the Development of PAH

Vasoreactivity Testing and Use of CCBs

Bosentan

Pregnancy

Conclusions

Acknowledgments

J Am Coll Cardiol

Chest

J Am Coll Cardiol

Mayo Clin Proc

J Am Coll Cardiol

J Am Coll Cardiol

Chest

Chest

J Am Coll Cardiol

J Am Coll Cardiol

Am J Med

Am Heart J

Chest

J Am Coll Cardiol

Lancet

Lancet

J Heart Lung Transplant

J Am Coll Cardiol

J Am Coll Cardiol

J Heart Lung Transplant

Chest

Chest

Mayo Clin Proc

Chest

Arch Bronconeumol

Chest

Chest

J Am Coll Cardiol

J Heart Lung Transplant

Chest

J Am Coll Cardiol

Br J Anaesth

Br J Anaesth

Chest

Obstet Gynecol

Am J Obstet Gynecol

Am J Obstet Gynecol

Chest

Respir Med

Circulation

Riociguat for the treatment of chronic thromboembolic pulmonary hypertension

N Engl J Med

IOM sets out “gold standard” practices for creating guidelines, systematic reviews

JAMA

Has the 6-min walk distance run its course?

Chest

Pulmonary Arterial Hypertension: Screening, Management, and Treatment

The Cochrane Collaboration's tool for assessing risk of bias in randomised trials

BMJ

Evidence-Based Medicine
Featured
Pharmacologic Therapy for Pulmonary Arterial Hypertension in Adults: CHEST Guideline and Expert Panel Report