Advances in Managing Pulmonary Arterial Hypertension

Course Director

Roham T. Zamanian, MD, FCCP

Roham T. Zamanian, MD, FCCP
Assistant Professor of Medicine
Director, Adult Pulmonary Hypertension Clinical Service
Vera Moulton Wall Center for Pulmonary Vascular Disease
Division of Pulmonary & Critical Care Medicine
Stanford University School of Medicine
Stanford, California

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Part 2 of a 2-part series

Dr. Zamanian provides expert feedback to the questions submitted by your peers during a recent survey on this topic.


The second activity in this series will feature answers to questions related to treatment of pulmonary arterial hypertension (PAH), particularly at earlier stages of disease. Conventional treatment for PAH has included the use of calcium channel antagonists (nifedipine, diltiazem, amlodipine), anticoagulants, diuretics, oxygen, and digoxin. More recently, improved understanding of the disease pathways in PAH has led to development and approval of three classes of drugs for the treatment of PAH: prostanoids, ERAs, and PDE‐5 inhibitors. All three drug classes have demonstrated improvements in hemodynamic parameters as well as functional capacity and exercise tolerance.


This activity is supported by educational grants from Actelion Pharmaceuticals US, Inc. and Bayer HealthCare. Additional support provided by Penn State College of Medicine and Answers in CME.

Course Director
Roham T. Zamanian, MD, FCCP, has a financial interest/relationship or affiliation in the form of:
Consultant for Actelion Pharmaceuticals US, Inc.; Bayer; and United Therapeutics Corporation.
Grant/Research Support from Actelion Pharmaceuticals US, Inc. and United Therapeutics Corporation.
Medical Director
Annette Wiggins
Answers in CME, Inc.
Annette Wiggins has no financial interests/relationships or affiliations in relation to this activity.

Answers in CME staff who may potentially review content for this activity have disclosed no relevant financial relationships.

Penn State College of Medicine staff and faculty involved in the development and review of this activity have disclosed no relevant financial relationships.

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What is the best approach to managing a 55-year-old woman who is diagnosed after right heart catheterization with idiopathic [pulmonary arterial hypertension, or] PAH functional class II? The patient had complained of recent onset of worsening dyspnea on mild exertion.

Dr. Zamanian: The treatment guidelines begin with the evaluation of response to a vasodilator challenge during a right heart catheterization, which should be performed as standard for every idiopathic patient. And if a patient is responsive to the vasoreactive challenge—either by nitric oxide testing, adenosine, or even prostacyclin in the cath lab—then the patient can receive calcium channel blockers and expect a substantial improvement.1 Once there is no vasoreactive response, then that patient can be characterized in a high-risk versus a low-risk stratification. The guidelines recommend evaluation of this patient in terms of their risk stratification.1

Low-risk patients are typically those who have a relatively normal or maintained 6-minute walking distance, a functional class that is lower—like in this case, a functional class II patient. A patient who does not have a severe hemodynamic perturbation, such as a cardiac index <2, that would be a patient that would be more severe, or right atrial pressure that is very high. So if a patient is really in a lower-risk category, then those are patients that are typically best managed on oral therapies in terms of phosphodiesterase inhibitors and endothelin receptor antagonists [ERA].1

Patients who have substantial risk are those patients with New York Heart Association [NYHA] Class IV symptoms and NT-proBNP [N-terminal pro-brain natriuretic peptide] that is very elevated. One could argue that their oxygen consumption and their VO2 maximum are very limited, and their 6-minute walking distance is less than about 300 meters. Those high-risk patients then deserve consideration for aggressive upfront treatment and use of prostacyclin therapies.1

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When is combination therapy indicated for patients with PAH?

Dr. Zamanian: This is a very important and interesting question that is currently being evaluated and answered. The latest guidelines continue to recommend the initiation of monotherapy, continued evaluation of response to that therapy, and additional therapeutics introduced if patients don't have a substantial response.1 However, the current guidelines don't have specific recommendations for combination upfront therapies. The guidelines do recognize that patients at higher risk, including NYHA Class IV patients who are rapidly deteriorating, can benefit from the combination of these therapies very quickly.1  

So at this point, we have to wait and see the results of both the reported retrospective analyses, but also prospective studies, such as the AMBITION study and others, in terms of a combination therapy upfront.2 The AMBITION study randomizes treatment-naïve PAH patients into three arms. These patients will either receive upfront ambrisentan as an ERA, upfront tadalafil as a phosphodiesterase-5 inhibitor, or a combination of ambrisentan plus tadalafil.3 And the goal of the AMBITION study is to look at the impact of monotherapy versus dual upfront therapy. This study is nearly completed in its enrollment. The results should be available within the next year or two.

The only other study that is a combination upfront therapy is a study that actually I designed and I'm running out of four centers in the United States. We call that study the CONFRONT-PAH study.4 The CONFRONT-PAH study randomized treatment-naïve patients into tadalafil alone versus tadalafil plus inhaled treprostinil. It is a study that is of six months in duration and with a primary endpoint of cardiac MRI, the performance of the right ventricle over a 6-month period.

Now, there is a component of combination therapy that should be clarified here. Patients typically are treated in combination as they advance due to disease. It is usual that physicians add therapies and do not take away prior therapies that the patients have [been] deemed to [have] failed on, but at this point that is considered a step-up therapy approach rather than a combination upfront.

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What novel therapies are in development for PAH, and how will they be incorporated into the current treatment algorithm?

Dr. Zamanian: The emerging therapies in the field of pulmonary vascular diseases currently are therapies that are either novel for the condition that the patients exhibit, which are out of the perspective of PAH, such as the evaluation of riociguat, which is a guanylate cyclase activator for patients with chronic thromboembolic pulmonary hypertension. It is one that is also unique in that it's been tested for patients with PAH on treatment, and it's also been studied in patients with inoperable chronic thromboembolic pulmonary hypertension, to remove the clot burden, or those patients who have had recurrent pulmonary hypertension post-thromboendarterectomy.5,6 And there is a lot of excitement about the data.

But the field has moved towards therapies that are not only vasodilators, but really the emergence of therapies that are antiproliferative. And in general, the science now is that if there will be a cure for PAH, the antiproliferative therapies will be the ones that will hopefully be disease-modifying.

This approach is seen in the evaluation of imatinib for pulmonary arterial hypertension, and the recognition that imatinib in phase 2 studies was of substantial benefit in patients specifically with pulmonary vascular resistances that were above 1,000 dynes·s·cm-5.7,8

These therapies are not only limited for patients with severe disease, but really are at this point aimed for patients who have had progressive disease in spite of triple therapies and are either bound towards transplantation or ones that basically have come to an end of therapeutic capacity.

There are experimental therapies that potentially modulate the bone morphogenic receptor-2 pathway, which is the genetic pathway that is primarily focused [on] in PAH therapies, such as tacrolimus. FK506 [tacrolimus] is currently being evaluated for this condition.9 But in general, these are therapies that will be added on once the currently approved therapies have been exhausted.

It has to be recognized that antiproliferative therapies have their own unique side-effect profiles. As we see with imatinib, there is a concern for potential CNS hemorrhagic conditions and intracranial bleeding.7 So physicians in the field now recognize that often these antiproliferative therapies, carry with them a side-effect profile that we're not routinely used to.

There is growing excitement in terms of immunomodulatory and immunosuppression therapies in PAH. It's recognized now that inflammation is a major part of PAH development, and there are ongoing trials such as rituximab for scleroderma-associated PAH patients that are being evaluated.10  

The current therapies that are approved have all received their regulatory approval based on the improvement in 6-minute walking distance. However, the field of experts recognizes that there are limitations to that evaluation as a primary endpoint.

So I think that we in the field are moving towards not only novel therapies, but a way to evaluate the response of these patients in a more robust way. And I think that the field recognizes that time to clinical worsening or an event-driven study is increasingly meaningful.

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  1. McLaughlin VV et al. Circulation. 2009;119:2250-2294.
  2. Taguchi H et al. Circ J. 2012;76:1494-500.
  3. Trial Identifier NCT01178073. Accessed May 13, 2013.
  4. Trial Identifier NCT01305252. Accessed May 13, 2013.
  5. Ghofrani HA et al. Eur Respir J. 2010;36:792-799.
  6. Kim NH. Eur Respir Rev. 2010;19:68-71.
  7. Hoeper MM et al. Circulation. 2013;127:1128-1138.
  8. Ghofrani HA et al. Am J Respir Crit Care Med. 2010;182:1171-1177.
  9. Trial Identifier NCT01647945. Accessed May 13, 2013.
  10. Trial Identifier NCT01086540. Accessed May 13, 2013.

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Actelion Pharmaceuticals US, Inc. Bayer HealthCare

This activity is supported by educational grants from Actelion Pharmaceuticals US, Inc. and Bayer HealthCare.
Additional support provided by Penn State College of Medicine and Answers in CME.

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Achieving Better Outcomes in the Management of Pulmonary Arterial Hypertension: Optimal Strategies for Early Diagnosis and Treatment

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